KR102361237B1 - Coiled coil immunoglobulin fusion proteins and compositions thereof - Google Patents

Abstract

Disclosed herein is an immunoglobulin fusion protein comprising a first antibody region, a first therapeutic agent, and a first linking peptide, wherein the first therapeutic agent is attached to the first antibody region by a linking peptide, and wherein the linking peptide is of the beta strand. An immunoglobulin fusion protein comprising no region having a secondary structure is disclosed. The connecting peptide may comprise an extender peptide. The extender peptide may have a secondary structure of an alpha helix. The linking peptide may comprise a linker peptide. The linker peptide may not include any secondary structure. Also disclosed herein are compositions comprising an immunoglobulin fusion protein and methods of using the immunoglobulin fusion protein to treat or prevent a disease or condition in a subject.

Description

COILED COIL IMMUNOGLOBULIN FUSION PROTEINS AND COMPOSITIONS THEREOF

Cross-reference of related applications

This application was filed on July 11, 2013 in U.S. Provisional Application No. 61/845,280, in U.S. Provisional Application No. 61/845,287, filed on July 11, 2013, and in U.S. Provisional Application No. 61, filed on January 10, 2014 /925,904, and U.S. Provisional Application No. 62/017,713, filed on June 26, 2014, all of which are incorporated herein by reference in their entirety.
sequence list
This application contains a sequence listing, submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. This ASCII copy, created on August 12, 2014, is named 41135-712.601_SL.txt and is 565,158 bytes in size.

background of the invention

Antibodies are natural proteins that the vertebrate immune system forms in response to foreign substances (antigens), primarily to defend against infection. For over a century, antibodies have been induced and collected in animals under artificial conditions for biological research or in the treatment or diagnosis of disease states. Although each individual antibody-producing cell produces a single type of antibody with a chemically defined composition, antibodies obtained directly from animal serum in response to antigenic challenge are actually non-identical molecules made up of an aggregate of individual antibody-producing cells (e.g., , polyclonal antibodies).

Antibody fusion constructs can be used to enhance delivery of drugs or other agents to target cells, tissues, and tumors. Antibody fusion constructs may include chemical linkers that attach drugs or other agents to the antibody. Representative antibody fusion constructs and methods of making antibody fusion constructs are disclosed in US Patent Application Nos. 2006/0182751, 2007/0160617, and US Patent No. 7,736,652.

Disclosed herein are novel immunoglobulin fusion proteins and methods for preparing the immunoglobulin fusion proteins. Also disclosed herein is the use of immunoglobulin fusion proteins for the treatment of various diseases and conditions. Also disclosed herein are methods of half-life of therapeutic agents.

In one aspect of the present disclosure, an immunoglobulin fusion protein comprising a first antibody region, a first therapeutic agent, and a first connecting peptide, wherein the first therapeutic agent is attached to the first antibody region by a connecting peptide, and the connecting peptide Provided herein are immunoglobulin fusion proteins wherein the β does not comprise a region having a secondary structure of the beta strand.

In one embodiment, the connecting peptide comprises a first extender peptide. The first extender peptide may comprise one or more regions having an alpha helix secondary structure. In some instances, the first extender peptide does not comprise more than 7 contiguous amino acids based on or derived from the bovine ultralong CDR3 amino acid sequence.

In one embodiment, the linking peptide comprises a first linking peptide. The first linking peptide may not include an alpha helix or beta strand secondary structure. The first linking peptide may comprise from about 0 to about 50 amino acids.

In one embodiment, the connecting peptide comprises from about 0 to about 50 amino acids. The linking peptide may comprise from about 4 to about 100 amino acids.

In one embodiment, the first connecting peptide is attached to a CDR of the first antibody region. In one embodiment, one or more regions of the first antibody region are substituted with a first therapeutic peptide. In another embodiment, one or more regions of the first antibody region are substituted with a first connecting peptide.

In one embodiment, the immunoglobulin fusion protein further comprises a second connecting peptide. In one embodiment, the second connecting peptide does not comprise a region having a secondary structure of the beta strand. The second connecting peptide may comprise a second extender peptide. The second extender peptide may comprise one or more regions having an alpha helix secondary structure. The second peptide may comprise a second linking peptide. The second linking peptide may not include an alpha helix or beta strand secondary structure.

In one embodiment, the immunoglobulin fusion protein further comprises a second therapeutic agent.

In one embodiment, the first antibody region comprises an amino acid sequence based on or derived from any one of SEQ ID NOs: 19-36 and 271-273. In one embodiment, the first antibody region comprises an amino acid sequence that is at least about 50% identical and/or homologous to an amino acid sequence of any one of SEQ ID NOs: 19-36 and 271-273. In one embodiment, the first antibody region comprises an amino acid sequence that is at least about 80% identical and/or homologous to an amino acid sequence of any one of SEQ ID NOs: 19-36 and 271-273.

In one embodiment, the first antibody region comprises an amino acid sequence based on or derived from a trastuzumab immunoglobulin. In one embodiment, the first antibody region comprises an amino acid sequence that is at least about 50% identical and/or homologous to the amino acid sequence of a trastuzumab immunoglobulin. In one embodiment, the first antibody region comprises an amino acid sequence that is at least about 80% identical and/or homologous to the amino acid sequence of a trastuzumab immunoglobulin.

In one embodiment, the first antibody region comprises an amino acid sequence based on or derived from palivizumab immunoglobulin. In one embodiment, the first antibody region comprises an amino acid sequence that is at least about 50% identical and/or homologous to the amino acid sequence of a palivizumab immunoglobulin. In one embodiment, the first antibody region comprises an amino acid sequence that is at least about 80% identical and/or homologous to the amino acid sequence of a palivizumab immunoglobulin.

In one embodiment, the immunoglobulin fusion protein further comprises a second antibody region. In some instances, the first antibody region comprises a region of an antibody light chain and the second antibody region comprises a region of an antibody heavy chain. In some instances, the first antibody region comprises a region of an antibody heavy chain and the second antibody region comprises a region of an antibody light chain. In some instances, the first antibody region comprises a first region of an antibody light chain and the second antibody region comprises a second region of an antibody light chain. In some instances, the first antibody region comprises a first region of an antibody heavy chain and the second antibody region comprises a second region of an antibody heavy chain. In one embodiment, the second antibody region comprises an amino acid sequence based on or derived from any one of SEQ ID NOs: 19-36 and 271-273. In one embodiment, the second antibody region comprises an amino acid sequence that is at least about 50% identical and/or homologous to an amino acid sequence of any one of SEQ ID NOs: 19-36 and 271-273. In one embodiment, the second antibody region comprises an amino acid sequence that is at least about 80% identical and/or homologous to the amino acid sequence of any one of SEQ ID NOs: 19-36 and 271-273.

In one embodiment, the second antibody region comprises an amino acid sequence based on or derived from trastuzumab immunoglobulin. In one embodiment, the second antibody region comprises an amino acid sequence that is at least about 50% identical and/or homologous to the amino acid sequence of a trastuzumab immunoglobulin. In one embodiment, the second antibody region comprises an amino acid sequence that is at least about 80% identical and/or homologous to the amino acid sequence of a trastuzumab immunoglobulin. In one embodiment, the second antibody region comprises an amino acid sequence based on or derived from palivizumab immunoglobulin. In one embodiment, the second antibody region comprises an amino acid sequence that is at least about 50% identical and/or homologous to the amino acid sequence of a palivizumab immunoglobulin. In one embodiment, the second antibody region comprises an amino acid sequence that is at least about 80% identical and/or homologous to the amino acid sequence of a palivizumab immunoglobulin.

In one embodiment, the first connecting peptide comprises an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-176, 179-185 and 275-277. In one embodiment, the first connecting peptide comprises an amino acid sequence that is at least about 50% identical and/or homologous to an amino acid sequence of any one of SEQ ID NOs: 144-176, 179-185 and 275-277. In one embodiment, the first connecting peptide comprises an amino acid sequence that is at least about 80% identical and/or homologous to an amino acid sequence of any one of SEQ ID NOs: 144-176, 179-185 and 275-277.

In one embodiment, the second connecting peptide comprises an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-176, 179-185 and 275-277. In one embodiment, the second connecting peptide comprises an amino acid sequence that is at least about 50% identical and/or homologous to an amino acid sequence of any one of SEQ ID NOs: 144-176, 179-185 and 275-277. In one embodiment, the second connecting peptide comprises an amino acid sequence that is at least about 80% identical and/or homologous to the amino acid sequence of any one of SEQ ID NOs: 144-176, 179-185 and 275-277.

In one embodiment, the first connecting peptide comprises a protease cleavage site. In one embodiment, the second connecting peptide comprises a protease cleavage site. In some instances, the first therapeutic agent comprises an amino acid sequence configured to be recognized by a protease. In some instances, the second therapeutic agent comprises an amino acid sequence configured to be recognized by a protease.

In one embodiment, the first connecting peptide comprises one or more extender peptides and one or more linker peptides. In one embodiment, the first connecting peptide comprises one or more extender peptides, one or more linker peptides, and one or more protease cleavage sites. In one embodiment, the first connecting peptide comprises one or more extender peptides and one or more protease cleavage sites. In one embodiment, the first connecting peptide comprises one or more linker peptides and one or more protease cleavage sites.

In one embodiment, the second connecting peptide comprises one or more extender peptides and one or more linker peptides. In one embodiment, the second connecting peptide comprises one or more extender peptides, one or more linker peptides, and one or more protease cleavage sites. In one embodiment, the second connecting peptide comprises one or more extender peptides and one or more protease cleavage sites. In one embodiment, the second connecting peptide comprises one or more linker peptides and one or more protease cleavage sites.

In one embodiment, the first therapeutic agent comprises an amino acid sequence based on or derived from any one of SEQ ID NOs: 227-267. In one embodiment, the first therapeutic agent comprises an amino acid sequence that is at least about 50% identical and/or homologous to an amino acid sequence of any one of SEQ ID NOs: 227-267. In one embodiment, the first therapeutic agent comprises an amino acid sequence that is at least about 80% identical and/or homologous to an amino acid sequence of any one of SEQ ID NOs: 227-267. In one embodiment, the first therapeutic agent comprises from about 5 to about 1,000 amino acids comprising about 5 to about 350 amino acids identical and/or homologous to any one of SEQ ID NOs: 227-267.

In one embodiment, the immunoglobulin fusion protein comprises an amino acid sequence based on or derived from any one of SEQ ID NOs: 68-99. In one embodiment, the immunoglobulin fusion protein comprises an amino acid sequence that is at least about 50% identical and/or homologous to an amino acid sequence of any one of SEQ ID NOs: 68-99. In one embodiment, the immunoglobulin fusion protein comprises an amino acid sequence that is at least about 80% identical and/or homologous to an amino acid sequence of any one of SEQ ID NOs: 68-99. In one embodiment, the immunoglobulin fusion protein comprises from about 5 to about 3,000 amino acids, comprising from about 50 to about 700 amino acids identical and/or homologous to any one of SEQ ID NOs: 68-99.

In another aspect, provided herein is a first genetic construct comprising a nucleic acid encoding an immunoglobulin fusion protein of any one of SEQ ID NOs: 68-99. In one embodiment, the first genetic construct comprises a nucleic acid derived from any one of SEQ ID NOs: 37-67. In one embodiment, the first genetic construct comprises a nucleic acid sequence that is at least about 50% identical and/or homologous to any one of SEQ ID NOs: 37-67. In one embodiment, the first genetic construct comprises a nucleic acid sequence that is at least about 80% identical and/or homologous to any one of SEQ ID NOs: 37-67.

In another aspect, provided herein is a first expression vector comprising a first gene construct comprising a nucleic acid encoding an immunoglobulin fusion protein of any one of SEQ ID NOs: 68-99. In one embodiment, provided herein is a first expression vector comprising a first gene construct comprising a nucleic acid derived from any one of SEQ ID NOs: 37-67. In one embodiment, provided herein is a first expression vector comprising a first gene construct comprising a nucleic acid sequence that is at least about 50% identical and/or homologous to any one of SEQ ID NOs: 37-67. In one embodiment, provided herein is a first expression vector comprising a first gene construct comprising a nucleic acid sequence that is at least about 80% identical and/or homologous to any one of SEQ ID NOs: 37-67. In some instances, provided herein is a mammalian expression host comprising a first expression vector. In one embodiment, there is provided a method of making an immunoglobulin fusion protein comprising the steps of (a) transiently transfecting a first expression vector in a mammalian cell culture, (b) at a controlled temperature and percentage of CO ₂ in an expression medium Provided herein is a method comprising the steps of culturing a cell culture (c) and recovering the secreted immunoglobulin fusion protein. In one embodiment, the method of making an immunoglobulin fusion protein further comprises purifying the immunoglobulin fusion protein.

In another aspect, there is provided a method of treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an immunoglobulin fusion protein comprising an amino acid sequence derived from any one of SEQ ID NOs: 68-99. Provided herein are methods comprising administering to In another aspect, there is provided a method of treating a disease or condition in a subject in need thereof, wherein the immunoglobulin comprises an amino acid sequence that is at least about 50% identical and/or homologous to any one of SEQ ID NOs: 68-99. Provided herein are methods comprising administering to a subject a therapeutically effective amount of a fusion protein. In another aspect, there is provided a method of treating a disease or condition in a subject in need thereof, comprising an immunoglobulin comprising an amino acid sequence that is at least about 80% identical and/or homologous to any one of SEQ ID NOs: 68-99. Provided herein are methods comprising administering to a subject a therapeutically effective amount of a fusion protein.

In another aspect, provided herein is a pharmaceutical composition comprising an immunoglobulin fusion protein derived from any one of SEQ ID NOs: 68-99. In another aspect, provided herein is a pharmaceutical composition comprising an immunoglobulin fusion protein comprising an amino acid sequence that is at least about 50% identical and/or homologous to any one of SEQ ID NOs: 68-99. In another aspect, provided herein is a pharmaceutical composition comprising an immunoglobulin fusion protein comprising an amino acid sequence that is at least about 80% identical and/or homologous to any one of SEQ ID NOs: 68-99. In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

In one embodiment, the immunoglobulin fusion protein comprises an amino acid sequence based on or derived from any one of SEQ ID NOs: 122-143. In one embodiment, the immunoglobulin fusion protein comprises an amino acid sequence that is at least about 50% identical and/or homologous to the amino acid sequence of any one of SEQ ID NOs: 122-143. In one embodiment, the immunoglobulin fusion protein comprises an amino acid sequence that is at least about 80% identical and/or homologous to the amino acid sequence of any one of SEQ ID NOs: 122-143. In one embodiment, the first immunoglobulin fusion protein comprises from about 5 to about 3,000 amino acids, comprising from about 50 to about 700 amino acids identical and/or homologous to any one of SEQ ID NOs: 122-143. .

In another aspect, provided herein is a first gene construct comprising a nucleic acid encoding an immunoglobulin fusion protein of any one of SEQ ID NOs: 122-143. In one embodiment, the first genetic construct comprises a nucleic acid derived from any one of SEQ ID NOs: 100-121. In one embodiment, the first genetic construct comprises a nucleic acid sequence that is at least about 50% identical and/or homologous to any one nucleic acid sequence of SEQ ID NOs: 100-121. In one embodiment, the first genetic construct comprises a nucleic acid sequence that is at least about 80% identical and/or homologous to any one of SEQ ID NOs: 100-121.

In another aspect, provided herein is a first expression vector comprising a first gene construct comprising a nucleic acid encoding an immunoglobulin fusion protein of any one of SEQ ID NOs: 122-143. In one embodiment, provided herein is a first expression vector comprising a first gene construct comprising a nucleic acid derived from any one of SEQ ID NOs: 100-121. In one embodiment, provided herein is a first expression vector comprising a first gene construct comprising a nucleic acid sequence that is at least about 50% identical and/or homologous to a nucleic acid sequence of any one of SEQ ID NOs: 100-121. In one embodiment, provided herein is a first expression vector comprising a first gene construct comprising a nucleic acid sequence that is at least about 80% identical and/or homologous to any one of SEQ ID NOs: 100-121. In some instances, provided herein is a mammalian expression host comprising a first expression vector. In one embodiment, there is provided a method of making an immunoglobulin fusion protein comprising the steps of (a) transiently transfecting a first expression vector in a mammalian cell culture, (b) at a controlled temperature and percentage of CO ₂ in an expression medium Provided herein is a method comprising the steps of culturing a cell culture (c) and recovering the secreted immunoglobulin fusion protein. In one embodiment, the method of making an immunoglobulin fusion protein further comprises purifying the immunoglobulin fusion protein.

In another aspect, there is provided a method of treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an immunoglobulin fusion protein comprising an amino acid sequence derived from any one of SEQ ID NOs: 122-143. Provided herein are methods comprising administering to In another aspect, there is provided a method of treating a disease or condition in a subject in need thereof, comprising an immunoglobulin comprising an amino acid sequence that is at least about 50% identical and/or homologous to any one of SEQ ID NOs: 122-143. Provided herein are methods comprising administering to a subject a therapeutically effective amount of a fusion protein. In another aspect, there is provided a method of treating a disease or condition in a subject in need thereof, wherein the immunoglobulin comprises an amino acid sequence that is at least about 80% identical and/or homologous to any one of SEQ ID NOs: 122-143. Provided herein are methods comprising administering to a subject a therapeutically effective amount of a fusion protein.

In another aspect, provided herein is a pharmaceutical composition comprising an immunoglobulin fusion protein derived from any one of SEQ ID NOs: 122-143. In another aspect, provided herein is a pharmaceutical composition comprising an immunoglobulin fusion protein comprising an amino acid sequence that is at least about 50% identical and/or homologous to any one of SEQ ID NOs: 122-143. In another aspect, provided herein is a pharmaceutical composition comprising an immunoglobulin fusion protein comprising an amino acid sequence that is at least about 80% identical and/or homologous to any one of SEQ ID NOs: 122-143. In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

In one embodiment, the first therapeutic peptide is configured to treat neutropenia and/or a neutropenia related disease. In one embodiment, the first therapeutic peptide is configured to treat diabetes and/or a diabetes related disease. In one embodiment, the first therapeutic peptide is configured to treat obesity and/or an obesity related disease. In one embodiment, the first therapeutic peptide is configured to treat an autoimmune disease and/or an autoimmune related disease. In one embodiment, the first therapeutic peptide is configured to treat anemia and/or anemia related disease. In one embodiment, the first therapeutic peptide is configured to treat a growth hormone deficiency and/or a growth hormone related disease. In one embodiment, the first therapeutic peptide is configured to treat chronic obstructive pulmonary disease (COPD) and/or a disease associated with COPD. In one embodiment, the first therapeutic peptide is configured to treat pain. In one embodiment, the first therapeutic peptide is configured to treat irritable bowel syndrome (IBS) and/or an IBS related disease. In one embodiment, the first therapeutic peptide is configured to treat Crohn's disease and/or Crohn's disease-associated disease. In one embodiment, the first therapeutic peptide is configured to treat neutropenia and/or a neutropenia related disease. In one embodiment, the first therapeutic peptide is configured to treat a metabolic disorder and/or a disease resulting from said metabolic disorder. In one embodiment, the metabolic disorder comprises lipodystrophy, diabetes, and hypertriglyceridemia. In one embodiment, the first therapeutic peptide is configured to treat short bowel syndrome and/or a disease associated with short bowel syndrome. In one embodiment, the first therapeutic peptide is configured to treat a patient with heart failure. In one embodiment, the first therapeutic peptide is configured to treat fibrosis and/or a fibrosis related disease.

In one embodiment, the immunoglobulin fusion protein is configured to treat neutropenia and/or a disease associated with neutropenia. In one embodiment, the immunoglobulin fusion protein is configured to treat diabetes and/or a diabetes related disease. In one embodiment, the immunoglobulin fusion protein is configured to treat obesity and/or an obesity related disease. In one embodiment, the immunoglobulin fusion protein is configured to treat an autoimmune disease and/or an autoimmune related disease. In one embodiment, the immunoglobulin fusion protein is configured to treat anemia and/or anemia-associated disease. In one embodiment, the immunoglobulin fusion protein is configured to treat a growth hormone deficiency and/or a growth hormone related disease. In one embodiment, the immunoglobulin fusion protein is configured to treat chronic obstructive pulmonary disease (COPD) and/or a disease associated with COPD. In one embodiment, the immunoglobulin fusion protein is configured to treat pain. In one embodiment, the immunoglobulin fusion protein is configured to treat irritable bowel syndrome (IBS) and/or an IBS related disease. In one embodiment, the immunoglobulin fusion protein is configured to treat Crohn's disease and/or Crohn's disease-associated disease. In one embodiment, the immunoglobulin fusion protein is configured to treat neutropenia and/or a disease associated with neutropenia. In one embodiment, the immunoglobulin fusion protein is configured to treat a metabolic disorder and/or a disease resulting from the metabolic disorder. In one embodiment, the metabolic disorder comprises lipodystrophy, diabetes, and hypertriglyceridemia. In one embodiment, the immunoglobulin fusion protein is configured to treat short bowel syndrome and/or a disease associated with short bowel syndrome. In one embodiment, the immunoglobulin fusion protein is configured to treat a patient with heart failure. In one embodiment, the immunoglobulin fusion protein is configured to treat fibrosis and/or a fibrosis related disease. In one embodiment, the first therapeutic peptide is configured to treat pulmonary arterial hypertension, ventilator-induced injury of immature lung and/or lung transplant rejection.

The above summary, and the following detailed description of the present disclosure, will be better understood when taken in conjunction with the accompanying drawings. For the purpose of illustrating the present disclosure, presently preferred embodiments are shown in the drawings. However, it should not be understood that the present disclosure is limited to the precise arrangements, embodiments and instrumentalities shown. It is emphasized that, by convention, the various individual parts of the drawings are not to scale. Conversely, the sizes of the various parts are arbitrarily enlarged or reduced for clarity.
In some figures, trastuzumab is represented by Herceptin. It should be understood that Trastuzumab and Herceptin may be used interchangeably throughout this specification. In some figures, immunoglobulin fusion proteins are described in the following order: antibody, coil or direct, therapeutic agent, and antibody region to which the therapeutic agent is attached; For example, trastuzumab-coil hEPO (CDRH3). Immunoglobulin fusion proteins can be described in any other way. For example, trastuzumab-CDRH3-coil-hEPO is the same fusion as trastuzumab-coil hEPO (CDRH3). In some instances, antibodies are abbreviated in the figures, eg bAb and BLVH12 are abbreviations for bovine antibody. PBS is the abbreviation for phosphate buffered saline. In some instances, hAb is an abbreviation for Herceptin or Trastuzumab antibody. In certain instances, H2 is an abbreviation for CDRH2, H3 is an abbreviation for CDRH3, and L3 is an abbreviation for CDRL3. In some instances, CDRH3 and CDR3H represent complementarity determining region 3 of a heavy chain, CDRH2 and CDR2H represent complementarity determining region 2 of a heavy chain, and CDRL3 and CDR3L represent complementarity determining region 3 of a light chain.
Provided herein are immunoglobulin fusion proteins comprising the term coil, in some cases immunoglobulin fusion proteins comprising at least one extender peptide comprising an amino acid having an alpha helix secondary structure. Provided herein are immunoglobulin fusion proteins comprising the term direct, and in some cases, immunoglobulin fusion proteins comprising no extender peptide.
The following [Fig.] is included in the drawings.
1 depicts a schematic diagram of several immunoglobulin fusion proteins with extender peptides comprising an alpha helix (eg, coil) structure.
2A-2G show schematics of various non-antibody regions.
3 shows a schematic of several immunoglobulin fusion proteins with extender peptides.
4 depicts SDS-PAGE gels of bovine-coil IgG, bovine-coil bGCSF IgG, trastuzumab IgG, and trastuzumab-coil bGCSF IgG.
Figure 5 depicts a schematic of several immunoglobulin fusion proteins with therapeutic peptides directly inserted into the antibody region.
6 depicts a graph of the in vitro activity of bovine-coil IgG, bovine-coil bGCSF IgG, Trastuzumab IgG, and Trastuzumab-coil bGCSF IgG in mouse NFS-60 cells.
7 depicts a graph of the binding affinity of trastuzumab-coil bGCSF IgG to the Her2 receptor.
[Fig. 8] shows a Western blot of DTT-treated and untreated BLV1H12-coil betatrophin IgG.
9 depicts a schematic of several immunoglobulin fusion proteins without extender peptides.
Figure 10 depicts SDS-PAGE of trastuzumab-direct bGCSF fusion protein with and without DTT treatment.
11 depicts a graph of the in vitro activity of trastuzumab-direct bGCSF fusion protein and bGCSF on mouse NFS-60 cell proliferation.
[Figure 12] shows the trastuzumab-coil exendin-4 (CDRH3) fusion protein and the trastuzumab-coil exendin-4 RN produced by the trastuzumab-coil exendin-4 fusion protein cleaved with factor Xa. SDS-PAGE gels are shown.
13 is a chromatograph of electrospary ionization mass spectrometry (ESI-MS) of trastuzumab-coil exendin-4 (CDRH3) fusion protein treated with peptide N-glucosidase and DTT. city
[Fig. 14A-14B] of trastuzumab-coil exendin-4 RN (CDRH3) fusion protein, (A) N-terminal fragment, (B) C-terminal fragment treated with peptide N - glucosidase and DTT. The chromatograph of ESI-MS is shown.
[Figure 15] GLP-1R receptor and cAMP responsive element (CRE: cAMP responsive element) - exendin-4 (Ex-4), trastuzumab, tra in HEK 293 cells overexpressing a luciferase (Luc) reporter Graphs of the in vitro activity of Stuzumab-coil exendin-4 (CDRH3), and Trastuzumab-coil exendin-4 (CDRH3) RN are shown.
Figure 16 shows glucagon, Ex-4, trastuzumab, trastuzumab-coil exendin-4 (CDRH3), and trastuzumab in HEK 293 cells overexpressing the glucagon receptor (GCGR) and CRE-Luc reporter. Depicts a graph of the in vitro activity of -coil exendin-4 (CDRH3) RN.
17A-17B depict graphs of the pharmacokinetics of (A) intravenous injection and (B) subcutaneous injection of trastuzumab-coil exendin-4 (CDRH3) IgG in mice.
18A-18R depict the pharmacodynamics of trastuzumab-coil exendin-4 (CDRH3) IgG at various time points in mice.
19A-19N depict pharmacokinetic properties at various time points of different concentrations of trastuzumab-coil exendin-4 (CDRH3) IgG in mice.
20 depicts SDS-PAGE gels of trastuzumab-coil Moka IgG and trastuzumab-coil Vm24 IgG with and without DTT treatment.
21 depicts a graph of the in vitro activity of trastuzumab-coil moka IgG and trastuzumab-coil Vm24 IgG upon T cell activation in human peripheral blood mononucleated cells (PBMC).
22 depicts SDS-PAGE of trastuzumab-coil hGCSF (CDRH2) and trastuzumab-coil hGCSF (CDRL3) with and without DTT treatment.
23A-23B show (A) trastuzumab-coil hGCSF (CDRH2) treated with peptide N-glucosidase and DTT, and (B) trastuzumab-treated with peptide N-glucosidase and DTT- Shows ESI-MS of coil hGCSF (CDRL3).
24 depicts histograms of trastuzumab-coil hGCSF (CDRH2) and trastuzumab-coil hGCSF (CDRL3) for the HER2 receptor.
25 depicts a graph of the in vitro activity of trastuzumab-coil hGCSF (CDRH2) and trastuzumab-coil hGCSF (CDRL3) on mouse NFS-60 cell proliferation.
Figure 26 depicts SDS-PAGE gels of trastuzumab-coil hEPO (CDRH3) treated and untreated with DTT.
27 depicts ESI-MS of Trastuzumab-coil hEPO (CDRH3) IgG treated with peptide N-glucosidase and DTT.
28 depicts a histogram of trastuzumab-coil hEPO (CDRH3) binding to the HER2 receptor.
29 depicts a graph of the in vitro activity of trastuzumab-coil hEPO (CDRH3) IgG on human TF-1 cell proliferation.
30 depicts an SDS-PAGE gel of double fusion trastuzumab-coil hEPO (CDRH3)-trastuzumab-coil hGCSF (CDRL3) IgG with and without DTT treatment.
[Figure 31A-31B] Light (A) and heavy (B) chains of double fusion trastuzumab-coil hEPO(CDRH3)-trastuzumab-coil hGCS (CDRL3) IgG treated with peptide N-glucosidase and DTT ESI-MS is shown.
32 depicts a histogram of dual fusion trastuzumab-coil hEPO (CDRH3)-trastuzumab-coil hGCSF (CDRL3) IgG binding to the HER2 receptor.
33 depicts a graph of the in vitro activity of dual fusion trastuzumab-coil hEPO (CDRH3)-trastuzumab-coil hGCSF (CDRL3) IgG on human TF-1 cell proliferation.
34 depicts a graph of the in vitro activity of double fusion trastuzumab-coil hEPO (CDRH3)-trastuzumab-coil hGCSF (CDRL3) IgG on proliferation of mouse NFS-60 cells.
[Figure 35] SDS-PAGE gel of trastuzumab-coil hGH (CDRH3) IgG, trastuzumab-direct fusion hGH (CDRH2) and trastuzumab-coil hGH (CDRH2) IgG after purification, with and without DTT treatment. shows
36A-36B depict pharmacokinetic properties of trastuzumab-coil hGH (CDRH3) IgG by (A) intravenous injection and (B) subcutaneous injection in rats.
37 depicts a graph showing the rate of change in body weight of rats injected with vehicle, genotropin, trastuzumab, and trastuzumab-coil hGH (CDRH3) IgG (indicated as Ab-GH in the figure).
38 shows SDS-PAGE gels of trastuzumab-coil hleptin (CDRH2), trastuzumab-coil hleptin (CDRH3), and trastuzumab-coil hleptin (CDRL3) with and without DTT treatment. do.
39A-39B show (A) hleptin, trastuzumab-coil h leptin (CDRH2), trastuzumab-coil h leptin (CDRH3), and (B) h leptin, on human leptin receptor (LepR) activation; A graph of the in vitro activity of trastuzumab-coil hleptin (CDRL3) is shown.
40A-40C depict histograms of cell binding of SKBR3 with wild-type (wt) trastuzumab, trastuzumab-coil hleptin (CDRH2), and trastuzumab-coil hleptin (CDRH3).
Figure 41 depicts an SDS-PAGE gel of trastuzumab-coil elafin (CDRH3) treated with and without DTT.
42A-42B depict graphs of in vitro inhibitory activity of trastuzumab-coil elafin (CDRH3).
Figure 43 depicts an SDS-PAGE gel of trastuzumab-coil GLP2 (CDRH3) treated and untreated with DTT.
Figure 44 depicts an SDS-PAGE gel of trastuzumab-coil relaxin (insulin c-peptide) (CDRH3) with and without DTT treatment.
45 depicts an SDS-PAGE gel of trastuzumab-coil relaxin (CDRH3) co-transfected with the cleaving enzyme prohormone convertase 2 (PC2) with and without DTT treatment.
Figure 46 depicts an SDS-PAGE gel of trastuzumab-coil relaxin (XTEN35) with 6x HIS (SEQ ID NO: 274) (CDRH3) IgG co-transfected with PC2, treated and untreated with DTT.

Disclosed herein are immunoglobulin fusion proteins and methods of making such immunoglobulin fusion proteins. An immunoglobulin fusion protein comprising an antibody region and a non-antibody region herein, wherein the non-antibody region comprises (a) a first extender peptide comprising at least one secondary structure and (b) a therapeutic agent. Initiate protein. The secondary structure may be an alpha helix. In some embodiments, the alpha helices are arranged to form a coiled coil. The therapeutic agent may be a therapeutic peptide. The non-antibody region may further comprise a linker. The linker may be a peptide linker. Peptide linkers may not have a typical secondary structure. The non-antibody region may further comprise a proteolytic cleavage site. In some embodiments, at least a portion of the antibody is substituted with a non-antibody region. In some embodiments, the extender peptide links the therapeutic agent to the antibody region. In some instances, the non-antibody region is linked to a CDR of an antibody. The CDR may be CDR1, CDR2, or CDR3. A CDR may be part of a light chain or a heavy chain. In an exemplary embodiment, the first extender peptide is a linking peptide or a portion of a linking peptide. In some embodiments, the peptide linker is a linking peptide or part of a linking peptide. In some embodiments, the protease cleavage site is a linking peptide or a portion of a linking peptide.

Also provided herein is an immunoglobulin fusion protein comprising an antibody region and an extender fusion region, wherein the extender fusion region comprises (a) a first extender peptide comprising an amino acid sequence comprising an alpha helical or coiled coil secondary structure; and (b) ), wherein the immunoglobulin fusion protein comprises a therapeutic agent. The therapeutic agent may be a therapeutic peptide. The extender fusion region may further comprise a linker. A linker peptide may comprise a linker. Peptide linkers may not have a typical secondary structure. The extender fusion region may further comprise a proteolytic cleavage site. In some embodiments, at least a portion of the antibody is substituted with an extender fusion region. In some embodiments, the extender peptide links the therapeutic agent to the antibody region. In some cases, the extender fusion region is linked to a CDR of an antibody. The CDR may be CDR1, CDR2, or CDR3. A CDR may be part of a light chain or a heavy chain. In an exemplary embodiment, the first extender peptide is a linking peptide or a portion of a linking peptide. In some embodiments, the peptide linker is a linking peptide or part of a linking peptide. In some embodiments, the protease cleavage site is a linking peptide or a portion of a linking peptide.

Also disclosed herein is an immunoglobulin fusion protein comprising an antibody region directly attached to a non-antibody region, wherein the non-antibody region comprises a therapeutic agent. The immunoglobulin fusion protein, in some instances, may be referred to as a direct immunoglobulin fusion protein. In some instances, the therapeutic agent is a therapeutic peptide. In some embodiments, the therapeutic agent is attached to the antibody region without the use of a peptide comprising a secondary structure. In some embodiments, the therapeutic agent replaces at least a portion of the antibody region to which the therapeutic agent is attached. In some embodiments, the therapeutic peptide is attached to the antibody region by one or more linkers that do not include common secondary structures (eg, alpha helices or beta strands). In some embodiments, the linker is a peptide linker. In some embodiments, the immunoglobulin fusion protein further comprises one or more protease cleavage sites. In some embodiments, the therapeutic agent is attached to a CDR of the antibody. The CDR may be CDR1, CDR2, or CDR3. A CDR may be part of a light chain or a heavy chain. In an exemplary embodiment, the peptide linker is a linking peptide or part of a linking peptide. In some embodiments, the protease cleavage site is a linking peptide or a portion of a linking peptide.

Also disclosed herein is an immunoglobulin fusion protein comprising an antibody region directly attached to an extender fusion region, wherein the extender fusion region comprises a therapeutic agent. The immunoglobulin fusion protein, in some instances, may be referred to as a direct immunoglobulin fusion protein. In some instances, the therapeutic agent is a therapeutic peptide. In some embodiments, the therapeutic agent is attached to the antibody region without the use of a peptide comprising a secondary structure. In some embodiments, the therapeutic agent replaces at least a portion of the antibody region to which the therapeutic agent is attached. In some embodiments, the therapeutic peptide is attached to the antibody region by one or more linkers that do not include common secondary structures (eg, alpha helices or beta strands). In some embodiments, the linker is a peptide linker. In some embodiments, the immunoglobulin fusion protein further comprises one or more protease cleavage sites. In some embodiments, the therapeutic agent is attached to a CDR of the antibody. The CDR may be CDR1, CDR2, or CDR3. A CDR may be part of a light chain or a heavy chain. In an exemplary embodiment, the peptide linker is a linking peptide or a portion of a linking peptide. In some embodiments, the protease cleavage site is a linking peptide or a portion of a linking peptide.

Also provided herein is an immunoglobulin fusion protein comprising a first antibody region, a first therapeutic agent, and a first connecting peptide, wherein the first therapeutic agent is attached to the first antibody region by a connecting peptide, wherein the An immunoglobulin fusion protein comprising no region having a secondary structure is disclosed. In an exemplary embodiment, the first therapeutic agent and the first connecting peptide are components of a non-antibody region. In an exemplary embodiment, the first therapeutic agent and the first connecting peptide are components of an extender fusion region. In some embodiments, the connecting peptide comprises one or more extender peptides. In some embodiments, the linking peptide comprises one or more linking peptides. In some embodiments, the connecting peptide comprises one or more protease cleavage sites. In some embodiments, the first connecting peptide comprises one or more extender peptides and one or more linker peptides. In some embodiments, the first connecting peptide comprises one or more extender peptides, one or more linker peptides, and one or more protease cleavage sites. In some embodiments, the first connecting peptide comprises one or more extender peptides and one or more protease cleavage sites. In some embodiments, the first connecting peptide comprises one or more linker peptides and one or more protease cleavage sites.

Also provided herein is an immunoglobulin fusion protein comprising (a) a non-antibody region and (b) an antibody region, wherein the non-antibody region replaces at least a portion of an antibody on which the antibody region is based or derived. Initiate protein. At least a portion of the complementarity determining region may be substituted with a non-antibody region. At least a portion of the variable domain may be substituted with a non-antibody region. At least a portion of the constant domain may be substituted with a non-antibody region. At least a portion of the heavy chain may be substituted with a non-antibody region. At least a portion of the light chain may be substituted with a non-antibody region. The non-antibody region may comprise a therapeutic peptide. The non-antibody region may comprise a linking peptide.

Also provided herein is an immunoglobulin fusion protein comprising (a) an extender fusion region and (b) an antibody region, wherein the extender fusion region replaces at least a portion of an antibody on which the antibody region is based or derived therefrom. Initiate protein. At least a portion of the complementarity determining region may be substituted with the extender fusion region. The extender fusion region may replace at least a portion of the variable domain. The extender fusion region may replace at least a portion of the constant domain. The extender fusion region may replace at least a portion of the heavy chain. The extender fusion region may replace at least a portion of the light chain. The extender fusion region may comprise a therapeutic peptide. The extender fusion region may comprise a linking peptide.

Also disclosed herein are dual fusion proteins comprising two or more therapeutic agents attached to one or more antibody regions or fragments thereof. At least one therapeutic agent may be inserted into or attached to the antibody or fragment thereof. Two or more therapeutic agents may be inserted into or attached to the antibody or fragment thereof. The therapeutic agent may be substituted for at least a portion of the antibody or fragment thereof. In some instances, the dual fusion protein comprises two therapeutic agents attached to a heavy chain. In some cases, the dual fusion protein comprises two therapeutic agents attached to a light chain. In some instances, the dual fusion protein comprises one therapeutic agent attached to a heavy chain and another therapeutic agent attached to a light chain.

In some embodiments, the non-antibody region is an extender fusion region. In some instances, the extender fusion region comprises (a) a first extender peptide comprising one or more secondary structures, and (b) a therapeutic agent. The secondary structure may be an alpha helix. The secondary structure may be arranged to form a coiled coil. The therapeutic agent may be a therapeutic peptide. In some embodiments, the non-antibody region comprises a linker. A linker may not have a typical secondary structure. In some embodiments, the non-antibody region comprises a protease cleavage site.

In some embodiments, an extender peptide forms an alpha helix and can be arranged to form a coiled coil, wherein an immunoglobulin fusion protein comprising the extender peptide is referred to as a coiled coil immunoglobulin fusion protein. In some embodiments, an immunoglobulin fusion protein that does not include an extender peptide having a secondary structure is referred to as a direct immunoglobulin fusion protein.

The extender peptide may be based on or derived from a very long CDR3. The extender peptide may comprise up to 7 amino acids derived from a very long CDR3 sequence. Alternatively, or additionally, the extender peptide does not comprise an amino acid sequence based on or derived from a very long CDR3. The extender peptide may comprise one or more secondary structures. One or more secondary structures may be alpha helices.

A representative immunoglobulin fusion protein comprising two extender peptides comprising a coiled-coil structure (eg, each extender peptide has a secondary structure of an alpha helix) is shown in FIG. 1 . As shown in FIG. 1 , the antibody region 110 comprising two immunoglobulin heavy chains 115 and 120 and two immunoglobulin light chains 125 and 130 includes two extender peptides 140 and 145 and a therapeutic agent. attached to the non-antibody region 135 comprising 150 to generate immunoglobulin fusion proteins 160 , 170 , 180 . As shown in FIG. 1 , the immunoglobulin fusion protein 160 includes a non-antibody region attached to one of the immunoglobulin heavy chains of the antibody region. As shown in FIG. 1 , the immunoglobulin fusion protein 170 includes a non-antibody region attached to one of the immunoglobulin light chains of the antibody region. In addition, as shown in FIG. 1 , the immunoglobulin fusion protein 180 includes two non-antibody regions attached to two immunoglobulin chains of an antibody region. Two extender peptides may form a coiled coil. Two extender peptides can form antiparallel coiled coils.

A representative direct immunoglobulin fusion protein in which a non-antibody region/extender fusion region (eg, therapeutic agent) is directly inserted into an antibody without the aid of an extender peptide having a secondary structure is shown in FIG. 5 . As shown in FIG. 5 , an antibody region 1010 comprising two immunoglobulin heavy chains 1015 and 1020 and two immunoglobulin light chains 1025 and 1030 is attached to a non-antibody region 1050 to form immunoglobulin Fusion proteins (1060, 1070, 1080) are generated. As shown in FIG. 5 , the immunoglobulin fusion protein 1060 comprises a non-antibody region attached to one of the immunoglobulin heavy chains of the antibody region. As shown in FIG. 5 , the immunoglobulin fusion protein 1070 comprises a non-antibody region attached to one of the immunoglobulin light chains of the antibody region. 5, the immunoglobulin fusion protein 1080 includes two non-antibody regions attached to two immunoglobulin chains of an antibody region.

Another representative coiled coil immunoglobulin fusion protein is shown in FIG. 3 . Formula IA of FIG. 3 depicts an immunoglobulin fusion protein comprising an antibody region (A ¹ ) attached to an extender fusion region comprising an extender peptide (E ¹ ) attached to a therapeutic agent (T ¹ ).

Formula IIA of [FIG. 3] is an immunoglobulin fusion protein comprising an antibody region (A ¹ ) attached to an extender fusion region comprising two extender peptides (E ¹ and E ² ) attached to a therapeutic agent (T ¹ ) show

Formula IIIA in FIG. 3 depicts an immunoglobulin double fusion protein comprising two antibody regions (A ¹ and A ² ) attached to each other. The immunoglobulin dual fusion protein comprises (a) a first antibody region (A ¹ ) attached to a first extender fusion region comprising two extender peptides (E ¹ and E ² ) attached to a first therapeutic agent (T ¹ ) and (b) a second antibody region (A ² ) attached to a second extender fusion region comprising two extender peptides (E ³ and E ⁴ ) attached to a second therapeutic agent (T ² ).

Formula IVA of FIG. 3 is an antibody attached to an extender fusion region comprising a linker (L ¹ ) attached to a therapeutic agent (T ¹ ) and a linker positioned between two extender peptides (E ¹ and E ² ) and a therapeutic agent (T 1 ) An immunoglobulin fusion protein comprising region (A ¹ ) is shown.

Formula VA of [FIG. 3] has a proteolytic cleavage site and a therapeutic agent located between two extender peptides (E ¹ and E ² ) and an extender comprising a proteolytic cleavage site (P ¹ ) attached to the therapeutic agent (T ¹ ) An immunoglobulin fusion protein comprising an antibody region (A ¹ ) attached to the fusion region is shown. Formula VB of FIG. 3 depicts a truncated form of Formula VA, wherein the proteolytic cleavage site is cleaved by a protease, resulting in the liberation of one end of the therapeutic agent. An immunoglobulin fusion protein that can be cleaved to release the amino terminus of the therapeutic agent is denoted as RN by shortening the released N-terminus. For example, trastuzumab-coil hGH RN indicates that the N-terminus of hGH is liberated upon proteolytic cleavage.

In Formula VIA of [FIG. 3], a therapeutic agent, a linker, and a proteolytic cleavage site are located between two extender peptides (E ¹ and E ² ), and a therapeutic agent attached to the linker (L ¹ ) and a proteolytic cleavage site (P ¹ ) Shown is an immunoglobulin fusion protein comprising an antibody region (A ¹ ) attached to an extender fusion region comprising (T ¹ ). Formula VIB of FIG. 3 depicts a truncated form of Formula VIA, wherein the proteolytic cleavage site is cleaved by a protease, resulting in the liberation of one end of the therapeutic agent. An immunoglobulin fusion protein that can be cleaved to release the carboxyl terminus of the therapeutic agent is denoted as RC by shortening the released C-terminus. For example, trastuzumab-coil hGH RC indicates that the C-terminus of hGH is liberated upon proteolytic cleavage.

Formula VIIA in FIG. 3 depicts an immunoglobulin double fusion protein comprising two antibody regions (A ¹ and A ² ). The first antibody region (A ¹ ) comprises a therapeutic agent and a linker positioned between two extender peptides (E ¹ and E ² ) and a therapeutic agent (T ¹ ) having two linkers (L ¹ and L ² ) at each end is attached to the first extender fusion region. A second antibody region (A ² ) is attached to a second extender fusion region comprising a therapeutic agent (T ² ) attached to a proteolytic cleavage site (P ¹ ). Within the second extender fusion region are the therapeutic agent and two linkers (L ³ and L ⁴ ) flanked by a proteolytic cleavage site. There are two extender peptides (E ¹ and E ² ) flanked by a therapeutic agent, a proteolytic cleavage site and two linkers in the second extender region.

Formula VIIIA of [Figure 3] is two extender peptides (E ¹ and E ² ), two linkers (L ¹ and L ² ), two proteolytic cleavage sites (P ¹ and P ² ) and a therapeutic agent (T ¹ ) shows an immunoglobulin fusion protein comprising an antibody region (A ¹ ) attached to an extender fusion region comprising Formula VIIIB of FIG. 3 depicts a truncated form of Formula VIIIA, wherein proteolytic cleavage sites located at the N-terminus and C-terminus of the therapeutic agent are cleaved by a protease to thereby liberate the therapeutic agent from the immunoglobulin fusion protein. make it

Another exemplary immunoglobulin fusion protein without an extender peptide (direct immunoglobulin fusion protein) is shown in FIG. 9 . Formula IXA of FIG. 9 depicts an immunoglobulin fusion protein comprising an antibody region (A ¹ ) attached to a non-antibody region comprising a therapeutic agent (T ¹ ).

Formula XA in FIG. 9 depicts an immunoglobulin fusion protein comprising an antibody region (A ¹ ) attached to a non-antibody region comprising a linker (L ¹ ) attached to a therapeutic agent (T ¹ ). Formula XIA in FIG. 9 depicts an immunoglobulin double fusion protein comprising two antibody regions (A ¹ and A ² ) attached to each other. The immunoglobulin dual fusion protein comprises (a) a first antibody region (A ¹ ) attached to a first non-antibody region comprising a first therapeutic agent (T ¹ ) and (b) a second therapeutic agent (T ² ). 2 and a second antibody region attached to the non-antibody region.

Formula XIIA of [FIG. 9] is an immunoglobulin fusion protein comprising an antibody region (A ¹ ) attached to a non-antibody region comprising a linker (L ¹ ), a proteolytic cleavage site (P ¹ ), and a therapeutic agent (T ¹ ) wherein the proteolytic cleavage site is located between the linker and the therapeutic agent. A proteolytic cleavage site within the second non-antibody region is cleaved by the protease, resulting in liberation of one end of the second therapeutic agent.

Formula XIIIA of FIG. 9 depicts an immunoglobulin fusion protein comprising an antibody region (A ¹ ) attached to a non-antibody region comprising a proteolytic cleavage site (P ¹ ) attached to a therapeutic agent (T ¹ ). Formula XIIIB of Figure 9 is a truncated form of Formula XIIIA, wherein the proteolytic cleavage site is cleaved by a protease, resulting in liberation of one end of the therapeutic agent.

Formula XIVA of FIG. 9 is an immunoglobulin fusion comprising an antibody region (A ¹ ) attached to a non-antibody region comprising a linker (L ¹ ), a therapeutic agent (T ¹ ), and a proteolytic cleavage site (P ¹ ) The protein is shown, wherein the therapeutic agent is located between the linker and the proteolytic cleavage site. Formula XIVB of FIG. 9 is a truncated form of Formula XIVA, wherein the proteolytic cleavage site is cleaved by a protease, resulting in liberation of one end of the therapeutic agent.

Formula XVA of FIG. 9 depicts an immunoglobulin double fusion protein comprising two antibody regions (A ¹ and A ² ). A first antibody region (A ¹ ) is attached to a first non-antibody region comprising a therapeutic agent (T ¹ ) with two linkers (L ¹ and L ² ) at each end. A second antibody region (A ² ) is attached to a second non-antibody region comprising a second therapeutic agent (T ² ) attached to a proteolytic cleavage site (P ¹ ). Within the second non-antibody region are the therapeutic agent and two linkers (L ³ and L ⁴ ) flanked by a proteolytic cleavage site. A proteolytic cleavage site within the second non-antibody region is cleaved by the protease, resulting in liberation of one end of the therapeutic agent.

Formula XVIA of [FIG. 9] is an antibody region attached to a non-antibody region comprising two linkers (L ¹ and L ² ), two proteolytic cleavage sites (P ¹ and P ² ) and a therapeutic agent (T ¹ ) ( A ¹ ) shows an immunoglobulin fusion protein comprising Formula XVIB of FIG. 9 depicts a truncated form of Formula XVIA, wherein proteolytic cleavage sites located at the N-terminus and C-terminus of the therapeutic agent are cleaved by a protease, resulting in the therapeutic agent from the immunoglobulin fusion protein. to favor

Also disclosed herein are methods of treating a disease or condition in a subject in need thereof. The method may comprise administering to a subject an immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide and (b) a therapeutic agent; The extender peptide does not have a secondary structure comprising a beta strand. The method may comprise administering to a subject an immunoglobulin fusion protein comprising an antibody region attached to a non-immunoglobulin region, wherein the non-immunoglobulin region comprises (a) an extender peptide and (b) a therapeutic agent; , the extender peptide does not have a secondary structure comprising a beta strand. The method may comprise administering to a subject a direct immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises a therapeutic agent, wherein the therapeutic agent has an extender peptide having a secondary structure or attached to the antibody region without using a linking peptide. The method may comprise administering to a subject an immunoglobulin fusion protein comprising an antibody region attached to a non-immunoglobulin region, wherein the non-immunoglobulin region comprises a therapeutic agent, wherein the therapeutic agent has an extender having a secondary structure It is attached to the antibody region without the use of peptides or linking peptides. The method may comprise administering to the subject an immunoglobulin fusion protein comprising an antibody region attached to a therapeutic peptide via a connecting peptide.

Also disclosed herein are methods of extending the half-life of a therapeutic agent. The method may comprise attaching a therapeutic agent to the antibody region. The method may comprise attaching the therapeutic agent to the antibody region using one or more linker peptides that do not have a typical secondary structure. The method may comprise attaching a therapeutic agent to the antibody region using one or more protease cleavage sites. The method may comprise attaching a therapeutic agent to the extender fusion peptide. The method may comprise attaching the antibody region to the therapeutic agent using an extender fusion peptide. The method may comprise attaching a therapeutic agent to the linking peptide. The method may comprise attaching a therapeutic agent to the antibody region using a linking peptide.

Also disclosed herein are methods of extending the half-life of a therapeutic agent. The method may comprise attaching an antibody region to a therapeutic agent to generate an immunoglobulin fusion protein. The method may further comprise attaching one or more linkers or proteolytic cleavage sites to the immunoglobulin fusion protein. One or more linkers may be attached to the N- and/or C-terminus of the therapeutic agent. One or more proteolytic cleavage sites may be attached to the N- and/or C-terminus of the therapeutic agent. One or more proteolytic cleavage sites may be inserted into the therapeutic agent.

Also disclosed herein are methods of enhancing the delivery of therapeutic agents. The method may comprise attaching an extender peptide to the therapeutic agent. The method may further comprise attaching the antibody region to the extender peptide, therapeutic agent, or extender fusion peptide. The method may comprise attaching a therapeutic peptide directly to the antibody region. The method may comprise attaching a linking peptide to the therapeutic agent. The method may further comprise attaching the antibody region to the connecting peptide and therapeutic agent.

Also disclosed herein are methods of enhancing the delivery of therapeutic agents. The method may comprise attaching an antibody region to a therapeutic agent to generate an immunoglobulin fusion protein. The method may further comprise attaching one or more linkers or proteolytic cleavage sites to the immunoglobulin fusion protein. One or more linkers may be attached to the N- and/or C-terminus of the therapeutic agent. One or more proteolytic cleavage sites may be attached to the N- and/or C-terminus of the therapeutic agent. One or more proteolytic cleavage sites may be inserted into the therapeutic agent.

Before the present methods and compositions are described, it is to be understood that the present invention is not limited to the particular methods or compositions described, as such may, of course, vary. Moreover, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. The examples are presented to fully disclose and explain to those skilled in the art how to make and use the present invention, they are not intended to limit the scope of what the inventors regard as their invention, and are intended to indicate that the experiments below are all or the only experiments performed. is not doing Efforts have been made to ensure accuracy with respect to numbers used (eg amounts, temperature, etc.), but some experimental errors and deviations should be accounted for. Unless otherwise specified, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric or near atmospheric.

The term "homologous," "homology," or "percent homology" when used herein to describe an amino acid sequence or a nucleic acid sequence with respect to a reference sequence is defined by Karlin and Altschul (Proc. Natl. Acad. Sci). USA 87: 2264-2268, 1990), which can be determined using the formula described in Proc. Natl. Acad. Sci. USA 90:5873-5877, 1993). The above formula is included in the Basic Local Alignment Search Tool (BLAST) program of Altschul et al. J. Mol. Biol. 215: 403-410, 1990. Percent homology of sequences can be determined using the most current version of BLAST as of the filing date of this application.

Where a range of values is provided, it is understood that each intervening value to the tenth of the unit between the upper and lower limits of the range is also specifically disclosed, unless explicitly stated in the text. Each smaller range between any stated value or intervening value within the stated range and any other or intervening value is encompassed by the invention. The upper and lower limits of the smaller ranges may be included or excluded independently of the range, including each range in which either or both of the limit values are included in the smaller range or neither of the limit values are included in the smaller range. It is included in the invention subject to any limit values specifically excluded within the stated range.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some methods and materials that are now possible and preferred are described. All publications mentioned herein are incorporated herein by reference, which discloses and describes the methods and/or materials with which the publications are cited. This disclosure is intended to supersede all disclosures of the incorporated publications to the extent that they are objectionable.

As will be apparent to those skilled in the art upon reading this disclosure, each of the embodiments described and illustrated herein can be readily separated from or combined with the features of any other several embodiments without departing from the scope or spirit of the invention. It has distinct components and features. All recited methods can be performed in the order of the recited instances or in any other order logically possible.

It should be noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include the plural unless the text clearly indicates otherwise. Thus, for example, reference to "a cell" includes reference to a plurality of said cells and reference to "peptide" includes reference to one or more peptides and equivalents thereof, such as polypeptides known to those skilled in the art, and the like.

As used herein, an amino acid sequence based on another amino acid sequence includes one or more contiguous amino acid portions of another amino acid sequence. Contiguous amino acid portions include any number of amino acids in another amino acid sequence. A contiguous amino acid sequence consists of 1-10%, 1-20%, 10-20%, 10-30%, 20-30%, 20-40%, 30-40% of any contiguous amino acid region of another amino acid sequence. , 40-50%, 50-60%, 50-100%, 60-70%, 60-100%, 70-100%, 80-100%, 80-90%, 90-95%, 90-100% , or 1-100% identical.

The publications discussed herein are provided solely for their disclosure prior to the filing date of this application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. In addition, the publication date provided may be different from the actual publication date, which may require separate confirmation.

Immunoglobulin Fusion Proteins

The immunoglobulin fusion proteins disclosed herein may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. Immunoglobulin domains can be derived from humanized, human engineered antibodies or fully human antibodies. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. The mammalian antibody may be a mouse antibody. The mammalian antibody may be a non-human primate antibody.

The immunoglobulin fusion proteins disclosed herein may comprise a therapeutic agent that is a functional peptide. The immunoglobulin fusion protein may comprise a functional peptide grafted onto an antibody scaffold. The functional peptide may be a linear peptide. The functional peptide may be a modified cyclic peptide. Functional peptides may include peptides modified to include a β-hairpin structure. The β-hairpin structure may be trapped within the β-hairpin conformation by one or more bonds between two or more amino acid residues of the β-hairpin structure. The N-terminus and/or C-terminus of the functional peptide may be grafted into an extender fusion region of an immunoglobulin fusion protein. The N-terminus of the functional peptide may be grafted onto the first extender peptide of the extender fusion region and the C-terminus of the functional peptide may be grafted onto the second extender peptide of the extender fusion region. Functional peptides may include peptides that have been modified to include conformationally restricted peptides. A conformationally restricted peptide may have a significant enhancement in binding affinity and/or specificity for a target relative to the target's endogenous or naturally occurring binding partner. The endogenous or naturally occurring binding partner of the target may be a ligand or substrate of the target. As a non-limiting example, a conformationally restricted peptide may be a peptide comprising a β-hairpin structure. A conformationally restricted peptide may comprise a region that binds to the binding site of the target. The target may be a receptor. The target may be an enzyme. The binding site of the target can be either a ligand binding domain or a deep pocket of a substrate binding domain. The functional peptide or portion thereof may bind to a deep pocket of the ligand binding domain or substrate binding domain to block binding of the target ligand and/or substrate. The functional peptide or portion thereof may bind to a deep pocket of the ligand binding domain or substrate binding domain to partially block binding of the target ligand and/or substrate. The functional peptide or portion thereof may bind to a deep pocket of the ligand binding domain or substrate binding domain to completely block binding of the target ligand or substrate. The functional peptide or portion thereof is capable of binding to the surface of a ligand binding domain or a substrate binding domain. A functional peptide may be an agonist. The functional peptide may be an antagonist. The functional peptide may be an inhibitor. The functional peptide may be a ligand. The functional peptide may be a substrate.

The immunoglobulin fusion protein may comprise an amino acid sequence based on or derived from any one of SEQ ID NOs: 68-99, and 122-143. The immunoglobulin fusion protein may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 68-99, and 122-143. The immunoglobulin fusion protein is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 68-99, and 122-143. adult amino acid sequences. The immunoglobulin fusion protein may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 68-99, and 122-143. The immunoglobulin fusion protein may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 68-99, and 122-143.

The immunoglobulin fusion protein is an amino acid comprising at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids based on or derived from any one of SEQ ID NOs: 68-99, and 122-143. sequence may be included. The immunoglobulin fusion protein may comprise 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, an amino acid sequence comprising 450, 475, 450, 500 or more amino acids. The immunoglobulin fusion protein may comprise an amino acid sequence comprising 10 or more amino acids based on or derived from any one of SEQ ID NOs: 68-99, and 122-143. The immunoglobulin fusion protein may comprise an amino acid sequence comprising 50 or more amino acids based on or derived from any one of SEQ ID NOs: 68-99, and 122-143. The immunoglobulin fusion protein may comprise an amino acid sequence comprising at least 100 amino acids based on or derived from any one of SEQ ID NOs: 68-99, and 122-143. The immunoglobulin fusion protein may comprise an amino acid sequence comprising 200 or more amino acids based on or derived from any one of SEQ ID NOs: 68-99, and 122-143. The amino acids may be contiguous. Alternatively, or additionally, the amino acids are discontinuous.

The immunoglobulin fusion protein may be encoded by a nucleotide sequence based on or derived from any one of SEQ ID NOs: 37-67, and 100-121. The immunoglobulin fusion protein may be encoded by a nucleotide sequence that is at least about 50% homologous to any one of SEQ ID NOs: 37-67, and 100-121. The immunoglobulin fusion protein is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 37-67, and 100-121. may be encoded by an adult nucleotide sequence. The immunoglobulin fusion protein may be encoded by a nucleotide sequence that is at least about 70% homologous to any one of SEQ ID NOs: 37-67, and 100-121. The immunoglobulin fusion protein may be encoded by a nucleotide sequence that is at least about 80% homologous to any one of SEQ ID NOs: 37-67, and 100-121.

The immunoglobulin fusion protein is a nucleotide comprising 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more nucleotides based on or derived from any one of SEQ ID NOs: 37-67, and 100-121. may be encoded by the sequence. The immunoglobulin fusion protein is based on or derived from any one of SEQ ID NOs: 37-67, and 100-121, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, It may be encoded by a nucleotide sequence comprising 450, 475, 450, 500 or more nucleotides. The immunoglobulin fusion protein comprises a nucleotide sequence comprising at least 600, 650, 700, 750, 800, 850, 900, 950, 1000 or more nucleotides based on or derived from any one of SEQ ID NOs: 37-67, and 100-121; can be coded by The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising 1100, 1200, 1300, 1400, 1500 or more nucleotides based on or derived from any one of SEQ ID NOs: 37-67, and 100-121. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising at least 100 nucleotides based on or derived from any one of SEQ ID NOs: 37-67, and 100-121. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising at least 500 nucleotides based on or derived from any one of SEQ ID NOs: 37-67, and 100-121. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising at least 1000 nucleotides based on or derived from any one of SEQ ID NOs: 37-67, and 100-121. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising at least 1300 nucleotides based on or derived from any one of SEQ ID NOs: 37-67, and 100-121. The nucleotides may be contiguous. Alternatively, or additionally, the nucleotides are discontinuous.

The immunoglobulin fusion protein may further comprise one or more immunoglobulin light chains. The immunoglobulin fusion protein may comprise at least two immunoglobulin light chains. The immunoglobulin light chain may comprise one or more portions of an immunoglobulin light chain. The immunoglobulin light chain may be an immunoglobulin fusion light chain. An immunoglobulin fusion light chain comprises an immunoglobulin light chain and an antibody region derived from a therapeutic agent. The therapeutic agent may be attached to the antibody region by one or more connecting peptides. The immunoglobulin light chain may comprise an amino acid sequence based on or derived from any one of SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122. The immunoglobulin light chain may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122. The immunoglobulin light chain comprises at least about 60%, 65%, 70%, 75%, 80%, 85%, 90 %, 95%, or 97% homologous amino acid sequences. The immunoglobulin light chain may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122. The immunoglobulin light chain may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122.

The immunoglobulin light chain is based on or derived from any one of SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122 10, 20, 30, 40, 50, 60, 70, 80, 90 , an amino acid sequence comprising 100 or more amino acids. The immunoglobulin light chain is based on or derived from any one of SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122, 125, 150, 175, 200, 225, 250, 275, 300, 325 , 350, 375, 400, 425, 450, 475, 450, an amino acid sequence comprising 500 or more amino acids. The immunoglobulin light chain may comprise an amino acid sequence comprising 10 or more amino acids based on or derived from any one of SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122. The immunoglobulin light chain may comprise an amino acid sequence comprising 50 or more amino acids based on or derived from any one of SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122. The immunoglobulin light chain may comprise an amino acid sequence comprising 100 or more amino acids based on or derived from any one of SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122. The immunoglobulin light chain may comprise an amino acid sequence comprising 200 or more amino acids based on or derived from any one of SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122. The amino acids may be contiguous. Alternatively, or additionally, the amino acids are discontinuous.

The immunoglobulin light chain may be encoded by a nucleotide sequence based on or derived from any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 50% homologous to any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100. The immunoglobulin light chain comprises at least about 60%, 65%, 70%, 75%, 80%, 85%, 90 %, 95%, or 97% homologous nucleotide sequences. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 70% homologous to any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 80% homologous to any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100.

The immunoglobulin light chain is 10, 20, 30, 40, 50, 60, 70, 80, 90 based on or derived from any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100. , may be encoded by a nucleotide sequence comprising 100 or more nucleotides. The immunoglobulin light chain is 125, 150, 175, 200, 225, 250, 275, 300, 325 based on or derived from any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100. , 350, 375, 400, 425, 450, 475, 450, 500 or more nucleotides. The immunoglobulin light chain is 600, 650, 700, 750, 800, 850, 900, 950, 1000 based on or derived from any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100. It may be encoded by a nucleotide sequence comprising more than one nucleotide. The immunoglobulin light chain comprises a nucleotide sequence comprising 1100, 1200, 1300, 1400, 1500 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100; can be coded by The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 100 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100. The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 500 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100. The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 1000 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100. The immunoglobulin light chain may be encoded by a nucleotide sequence comprising at least 1300 nucleotides based on or derived from any one of SEQ ID NOs: 1-3, 10, 18, 37, 49, 63, 67, and 100. The nucleotides may be contiguous. Alternatively, or additionally, the nucleotides are discontinuous.

The immunoglobulin fusion protein may further comprise one or more immunoglobulin heavy chains. The immunoglobulin fusion protein may comprise at least two immunoglobulin heavy chains. An immunoglobulin heavy chain may comprise one or more portions of an immunoglobulin heavy chain. The immunoglobulin heavy chain may be an immunoglobulin fusion heavy chain. An immunoglobulin fusion heavy chain comprises an antibody region derived from an immunoglobulin heavy chain and a therapeutic agent. The therapeutic agent may be attached to the antibody region by one or more connecting peptides. The immunoglobulin heavy chain may comprise an amino acid sequence based on or derived from any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143. The immunoglobulin heavy chain may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143. . The immunoglobulin heavy chain comprises at least about 60%, 65%, 70%, 75% of any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143. , 80%, 85%, 90%, 95%, or 97% homologous amino acid sequences. The immunoglobulin heavy chain may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143. . The immunoglobulin heavy chain may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143. .

The immunoglobulin heavy chain is 10, 20, 30, 40, 50 based on or derived from any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143. , 60, 70, 80, 90, 100 or more amino acids. The immunoglobulin heavy chain is based on or derived from any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143 125, 150, 175, 200, 225 , 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 450, an amino acid sequence comprising 500 or more amino acids. an immunoglobulin heavy chain comprising an amino acid sequence comprising at least 10 amino acids based on or derived from any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143 may include an immunoglobulin heavy chain comprising an amino acid sequence comprising at least 50 amino acids based on or derived from any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143 may include an immunoglobulin heavy chain comprising an amino acid sequence comprising at least 100 amino acids based on or derived from any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143 may include an immunoglobulin heavy chain comprising an amino acid sequence comprising at least 200 amino acids based on or derived from any one of SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143 may include The amino acids may be contiguous. Alternatively, or additionally, the amino acids are discontinuous.

The immunoglobulin heavy chain may be encoded by a nucleotide sequence based on or derived from any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 50% homologous to any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121. The immunoglobulin heavy chain has at least about 60%, 65%, 70%, 75%, 80 %, 85%, 90%, 95%, or 97% homologous nucleotide sequences. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 70% homologous to any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 80% homologous to any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121.

The immunoglobulin heavy chain is 10, 20, 30, 40, 50, 60 based on or derived from any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121. , 70, 80, 90, 100 or more nucleotides. The immunoglobulin heavy chain is 125, 150, 175, 200, 225, 250 based on or derived from any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121. , 275, 300, 325, 350, 375, 400, 425, 450, 475, 450, 500 or more nucleotides. The immunoglobulin heavy chain is 600, 650, 700, 750, 800, 850 based on or derived from any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121 , 900, 950, 1000 or more nucleotides. The immunoglobulin heavy chain has at least 1100, 1200, 1300, 1400, 1500 or more based on or derived from any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121. It may be encoded by a nucleotide sequence comprising nucleotides. The immunoglobulin heavy chain comprises a nucleotide sequence comprising at least 100 nucleotides based on or derived from any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121; can be coded. an immunoglobulin heavy chain comprising a nucleotide sequence comprising at least 500 nucleotides based on or derived from any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121; can be coded. an immunoglobulin heavy chain comprising a nucleotide sequence comprising at least 1000 nucleotides based on or derived from any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121; can be coded. an immunoglobulin heavy chain comprising a nucleotide sequence comprising at least 1300 nucleotides based on or derived from any one of SEQ ID NOs: 4-9, 11-17, 38-48, 50-62, 64-66, and 101-121; can be coded. The nucleotides may be contiguous. Alternatively, or additionally, the nucleotides are discontinuous.

The immunoglobulin fusion protein comprises (a) a first immunoglobulin fusion heavy chain comprising an amino acid sequence based on or derived from SEQ ID NOs: 69-79, 81-93, 95-97, 99, and 123-143 and (b) the sequence and a first immunoglobulin light chain comprising an amino acid sequence based on or derived from Nos. 19-21, 28, and 36. The immunoglobulin fusion protein comprises (a) a first immunoglobulin fusion heavy chain comprising an amino acid sequence that is at least about 50% identical to SEQ ID NOs: 69-79, 81-93, 95-97, 99, and 123-143; and a first immunoglobulin light chain comprising an amino acid sequence that is at least about 50% identical to Nos. 19-21, 28, and 36. The first immunoglobulin fusion heavy chain comprises SEQ ID NOs: 69-79, 81-93, 95-97, 99, and 123-143 and at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97 % identical amino acid sequences. The first immunoglobulin light chain comprises an amino acid sequence that is at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97% identical to SEQ ID NOs: 19-21, 28, and 36.

The immunoglobulin fusion protein comprises (a) a first immunoglobulin fusion heavy chain encoded by the nucleotide sequences of SEQ ID NOs: 38-48, 50-62, 64-66, and 101-121 and (b) SEQ ID NOs: 1-3, 10 and a first immunoglobulin light chain encoded by the nucleotide sequence of 18. The immunoglobulin fusion protein comprises (a) a first immunoglobulin fusion heavy chain encoded by a nucleotide sequence that is at least 50% homologous to the nucleotide sequences of SEQ ID NOs: 38-48, 50-62, 64-66, and 101-121; b) a first immunoglobulin light chain encoded by a nucleotide sequence that is at least 50% or more homologous to the nucleotide sequence of SEQ ID NOs: 1-3, 10 and 18. The first immunoglobulin fusion heavy chain has a nucleotide sequence of SEQ ID NOs: 38-48, 50-62, 64-66, and 101-121 and at least 60%, 70%, 75%, 80%, 90%, 95%, or 97 It is encoded by a nucleotide sequence that is at least % homologous. The first immunoglobulin light chain is encoded by a nucleotide sequence that is at least 60%, 70%, 75%, 80%, 90%, 95%, or 97% or more homologous to the nucleotide sequence of SEQ ID NOs: 1-3, 10 and 18 .

The immunoglobulin fusion protein comprises (a) a first immunoglobulin heavy chain comprising amino acid sequences based on or derived from SEQ ID NOs: 22-27, and 29-35 and (b) SEQ ID NOs: 68, 80, 94, 98, and 122 and a first immunoglobulin fusion light chain comprising an amino acid sequence based on or derived therefrom. The immunoglobulin fusion protein comprises (a) a first immunoglobulin heavy chain comprising an amino acid sequence that is at least about 50% identical to SEQ ID NOs: 22-27, and 29-35 and (b) SEQ ID NOs: 68, 80, 94, 98, and 122 and a first immunoglobulin fusion light chain comprising an amino acid sequence that is at least about 50% identical to The first immunoglobulin heavy chain may comprise an amino acid sequence that is at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97% identical to SEQ ID NOs: 22-27, and 29-35. The first immunoglobulin fusion light chain comprises an amino acid sequence that is at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97% identical to SEQ ID NOs: 68, 80, 94, 98, and 122.

The immunoglobulin fusion protein comprises (a) a first immunoglobulin heavy chain encoded by the nucleotide sequences of SEQ ID NOs: 4-9 11-17 and (b) encoded by the nucleotide sequences of SEQ ID NOs: 37, 49, 63, 67, and 100 and a first immunoglobulin fusion light chain. The immunoglobulin fusion protein comprises (a) a first immunoglobulin heavy chain encoded by nucleotides that are at least 50% or more homologous to the nucleotide sequences of SEQ ID NOs: 4-9 and 11-17 and (b) SEQ ID NOs: 37, 49, 63, 67 , and a first immunoglobulin fusion light chain encoded by a nucleotide sequence that is at least 50% or more homologous to a nucleotide sequence of 100. The first immunoglobulin heavy chain is encoded by a nucleotide sequence that is at least 60%, 70%, 75%, 80%, 90%, 95%, or 97% homologous to the nucleotide sequences of SEQ ID NOs: 4-9 and 11-17 . The first immunoglobulin fusion light chain has a nucleotide sequence that is at least 60%, 70%, 75%, 80%, 90%, 95%, or 97% or more homologous to the nucleotide sequence of SEQ ID NOs: 37, 49, 63, 67, and 100 is coded by

The immunoglobulin fusion protein comprises (a) a first immunoglobulin fusion heavy chain comprising an amino acid sequence based on or derived from SEQ ID NOs: 69-79, 81-93, 95-97, 99, and 123-143 and (b) the sequence and a first immunoglobulin fusion light chain comprising an amino acid sequence based on or derived from Nos. 68, 80, 94, 98, and 122. The immunoglobulin fusion protein comprises (a) a first immunoglobulin fusion heavy chain comprising an amino acid sequence that is at least about 50% identical to SEQ ID NOs: 69-79, 81-93, 95-97, 99, and 123-143 and (b) the sequence and a first immunoglobulin fusion light chain comprising an amino acid sequence that is at least about 50% identical to Nos. 68, 80, 94, 98, and 122. The first immunoglobulin fusion heavy chain comprises SEQ ID NOs: 69-79, 81-93, 95-97, 99, and 123-143 and at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97 % identical amino acid sequences. The first immunoglobulin fusion light chain comprises an amino acid sequence that is at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97% identical to SEQ ID NOs: 68, 80, 94, 98, and 122.

The immunoglobulin fusion protein comprises (a) a first immunoglobulin fusion heavy chain encoded by the nucleotide sequences of SEQ ID NOs: 38-48, 50-62, 64-66, and 101-121 and (b) SEQ ID NOs: 37, 49, 63 , 67, and 100; and a first immunoglobulin fusion light chain encoded by the nucleotide sequence. The immunoglobulin fusion protein comprises (a) a first immunoglobulin fusion heavy chain encoded by a nucleotide sequence that is at least 50% homologous to the nucleotide sequences of SEQ ID NOs: 38-48, 50-62, 64-66, and 101-121; b) a first immunoglobulin fusion light chain encoded by a nucleotide sequence that is at least 50% or more homologous to the nucleotide sequence of SEQ ID NOs: 37, 49, 63, 67, and 100. The first immunoglobulin fusion heavy chain has a nucleotide sequence of SEQ ID NOs: 38-48, 50-62, 64-66, and 101-121 and at least 60%, 70%, 75%, 80%, 90%, 95%, or 97 It is encoded by a nucleotide sequence that is at least % homologous. The first immunoglobulin fusion light chain has a nucleotide sequence that is at least 60%, 70%, 75%, 80%, 90%, 95%, or 97% homologous to the nucleotide sequence of SEQ ID NOs: 37, 49, 63, 67, and 100 is coded by

Also herein, (a) the non-antibody region comprises (i) a first extender peptide comprising an amino acid sequence comprising a secondary structure of an alpha helix and no very long CDR3, and (ii) a first therapeutic agent; an antibody region attached to the non-antibody region; and (b) a second therapeutic agent. Attachment of the antibody region to the non-antibody region may comprise insertion of the non-antibody region into the antibody region. The first therapeutic agent and the second therapeutic agent may be the same. The first therapeutic agent and the second therapeutic agent may be different. The dual fusion protein may further comprise a second antibody region. The first and second therapeutic agents may be attached to the first antibody region. The first and second therapeutic agents may be attached to the first antibody region and the second antibody region, respectively. The first and second antibody regions may be linked. The first and second antibody regions may be linked by one or more disulfide bonds. The first and second antibody regions may be part of a light chain or a heavy chain of an immunoglobulin. The immunoglobulin dual fusion protein may further comprise one or more additional extender peptides. The immunoglobulin dual fusion protein may further comprise one or more linker peptides. The immunoglobulin dual fusion protein may further comprise one or more protease cleavage sites.

Alternatively, the immunoglobulin dual fusion protein comprises (a) the non-antibody region (i) comprising an amino acid sequence comprising the secondary structure of an alpha helix and not more than 7 amino acids based on or derived from an ultralong CDR3 a first extender peptide comprising a first extender peptide and (ii) an antibody region attached to said non-antibody region comprising a first therapeutic agent; and (b) a second therapeutic agent. Attachment of the antibody region to the non-antibody region may comprise insertion of the non-antibody region into the antibody region. The first therapeutic agent and the second therapeutic agent may be the same. The first therapeutic agent and the second therapeutic agent may be different. The dual fusion protein may further comprise a second antibody region. The first and second therapeutic agents may be attached to the first antibody region. The first and second therapeutic agents may be attached to the first antibody region and the second antibody region, respectively. The first and second antibody regions may be linked. The first and second antibody regions may be linked by one or more disulfide bonds. The first and second antibody regions may be part of a light chain or a heavy chain of an immunoglobulin. The immunoglobulin dual fusion protein may further comprise one or more additional extender peptides. The immunoglobulin dual fusion protein may further comprise one or more linker peptides. The immunoglobulin dual fusion protein may further comprise one or more protease cleavage sites.

Alternatively, the immunoglobulin dual fusion protein may comprise (a) a first extender peptide wherein the extender fusion region comprises (i) an amino acid sequence comprising the secondary structure of an alpha helix and no very long CDR3, and (ii) a first an antibody region comprising a therapeutic agent and attached to the extender fusion region; and (b) a second therapeutic agent. Attachment of the antibody region to the extender fusion region may comprise insertion of the extender fusion region into the antibody region. The first therapeutic agent and the second therapeutic agent may be the same. The first therapeutic agent and the second therapeutic agent may be different. The dual fusion protein may further comprise a second antibody region. The first and second therapeutic agents may be attached to the first antibody region. The first and second therapeutic agents may be attached to the first antibody region and the second antibody region, respectively. The first and second antibody regions may be linked. The first and second antibody regions may be linked by one or more disulfide bonds. The first and second antibody regions may be part of a light chain or a heavy chain of an immunoglobulin. The immunoglobulin dual fusion protein may further comprise one or more additional extender peptides. The immunoglobulin dual fusion protein may further comprise one or more linker peptides. The immunoglobulin dual fusion protein may further comprise one or more protease cleavage sites.

Alternatively, an immunoglobulin dual fusion protein may comprise a formulation comprising (a) the extender fusion region (i) comprising an amino acid sequence comprising the secondary structure of an alpha helix and comprising no more than 7 amino acids based on or derived from a very long CDR3 1 extender peptide, and (ii) an antibody region attached to the extender fusion region comprising a first therapeutic agent; and (b) a second therapeutic agent. Attachment of the antibody region to the extender fusion region may comprise insertion of the extender fusion region into the antibody region. The first therapeutic agent and the second therapeutic agent may be the same. The first therapeutic agent and the second therapeutic agent may be different. The dual fusion protein may further comprise a second antibody region. The first and second therapeutic agents may be attached to the first antibody region. The first and second therapeutic agents may be attached to the first antibody region and the second antibody region, respectively. The first and second antibody regions may be linked. The first and second antibody regions may be linked by one or more disulfide bonds. The first and second antibody regions may be part of a light chain or a heavy chain of an immunoglobulin. The immunoglobulin dual fusion protein may further comprise one or more additional extender peptides. The immunoglobulin dual fusion protein may further comprise one or more linker peptides. The immunoglobulin dual fusion protein may further comprise one or more protease cleavage sites.

Alternatively, the immunoglobulin double fusion protein comprises (a) a first linking peptide wherein the non-antibody region does not comprise (i) an amino acid sequence comprising an alpha helix or beta strand secondary structure, and (ii) a first therapeutic agent and an antibody region attached to the non-antibody region; and (b) a second therapeutic agent. Attachment of the antibody region to the non-antibody region may comprise insertion of the non-antibody region into the antibody region. The first therapeutic agent and the second therapeutic agent may be the same. The first therapeutic agent and the second therapeutic agent may be different. The dual fusion protein may further comprise a second antibody region. The first and second therapeutic agents may be attached to the first antibody region. The first and second therapeutic agents may be attached to the first antibody region and the second antibody region, respectively. The first and second antibody regions may be linked. The first and second antibody regions may be linked by one or more disulfide bonds. The first and second antibody regions may be part of a light chain or a heavy chain of an immunoglobulin. The immunoglobulin dual fusion protein may further comprise one or more additional linker peptides. The immunoglobulin dual fusion protein may further comprise one or more protease cleavage sites.

Alternatively, the immunoglobulin double fusion protein comprises (a) the extender fusion region comprises (i) a first linking peptide that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a first therapeutic agent; , an antibody region attached to the extender fusion region; and (b) a second therapeutic agent. Attachment of the antibody region to the extender fusion region may comprise insertion of the extender fusion region into the antibody region. The first therapeutic agent and the second therapeutic agent may be the same. The first therapeutic agent and the second therapeutic agent may be different. The dual fusion protein may further comprise a second antibody region. The first and second therapeutic agents may be attached to the first antibody region. The first and second therapeutic agents may be attached to the first antibody region and the second antibody region, respectively. The first and second antibody regions may be linked. The first and second antibody regions may be linked by one or more disulfide bonds. The first and second antibody regions may be part of a light chain or a heavy chain of an immunoglobulin. The immunoglobulin dual fusion protein may further comprise one or more additional linker peptides. The immunoglobulin dual fusion protein may further comprise one or more protease cleavage sites.

The dual fusion antibody comprises (a) a first non-antibody region comprising (i) a first extender peptide comprising an amino acid sequence comprising a secondary structure of an alpha helix and (ii) a first therapeutic agent, said first non-antibody region a first immunoglobulin fusion protein comprising a first antibody region attached to; and (b) the second non-antibody region comprises (i) a second extender peptide comprising at least one secondary structure and (ii) a second therapeutic agent, wherein the second antibody comprises a second antibody attached to the second non-antibody region. and a second immunoglobulin fusion protein. In some embodiments, the first extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the second extender peptide is a connecting peptide or part of a connecting peptide. In some embodiments, the first extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the second extender peptide does not comprise an amino acid having a secondary structure of the beta strand. The dual fusion antibody may further comprise one or more peptide linkers. The dual fusion antibody may further comprise one or more protease cleavage sites.

The dual fusion antibody comprises (a) a first non-antibody region comprising (i) a first extender peptide comprising an amino acid sequence comprising a secondary structure of an alpha helix and (ii) a first therapeutic agent, said first non-antibody region a first immunoglobulin fusion protein comprising a first antibody region attached to, and (b) an extender fusion region comprising (i) a second extender peptide comprising at least one secondary structure and (ii) a second therapeutic agent; , a second immunoglobulin fusion protein comprising a second antibody region attached to the extender fusion region. In some embodiments, the first extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the second extender peptide is a connecting peptide or part of a connecting peptide. The dual fusion antibody may further comprise one or more peptide linkers. The dual fusion antibody may further comprise one or more protease cleavage sites. In some embodiments, the first extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the second extender peptide does not comprise an amino acid having a secondary structure of the beta strand.

The dual fusion antibody comprises (a) a first extender fusion region comprising (i) a first extender peptide comprising an amino acid sequence comprising a secondary structure of an alpha helix and (ii) a first therapeutic agent, wherein the first extender fusion region comprises: a first immunoglobulin fusion protein comprising a first antibody region attached to; and (b) a second non-antibody region comprising (i) a second extender peptide comprising at least one secondary structure and (ii) a second therapeutic agent, wherein the second antibody region is attached to the non-antibody region. immunoglobulin fusion proteins. In some embodiments, the first extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the second extender peptide is a connecting peptide or part of a connecting peptide. The dual fusion antibody may further comprise one or more peptide linkers. The dual fusion antibody may further comprise one or more protease cleavage sites. In some embodiments, the first extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the second extender peptide does not comprise an amino acid having a secondary structure of the beta strand.

The dual fusion antibody comprises (a) a first extender fusion region comprising (i) a first extender peptide comprising an amino acid sequence comprising a secondary structure of an alpha helix and (ii) a first therapeutic agent, wherein the first extender fusion region comprises: a first immunoglobulin fusion protein comprising a first antibody region attached to; and (b) a second extender fusion region comprising (i) a second extender peptide comprising at least one secondary structure and (ii) a second therapeutic agent, wherein the second antibody region is attached to the extender fusion region. immunoglobulin fusion proteins. In some embodiments, the first extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the second extender peptide is a connecting peptide or part of a connecting peptide. The dual fusion antibody may further comprise one or more peptide linkers. The dual fusion antibody may further comprise one or more protease cleavage sites. In some embodiments, the first extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the second extender peptide does not comprise an amino acid having a secondary structure of the beta strand.

A dual fusion antibody comprises (a) (i) a first peptide linker wherein the first non-antibody region does not comprise an amino acid sequence comprising a secondary structure of an alpha helix or beta strand, and (ii) a first therapeutic agent; 1 a first immunoglobulin fusion protein comprising a first antibody region attached to a non-antibody region; and (b) the second non-antibody region comprises (i) a second peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a second therapeutic agent; and a second immunoglobulin fusion protein comprising a second antibody region attached to the region. In some embodiments, the first linker peptide is a linking peptide or part of a linking peptide. In some embodiments, the second linker peptide is a connecting peptide or part of a connecting peptide. The dual fusion antibody may further comprise one or more protease cleavage sites.

A dual fusion antibody comprises (a) a first non-antibody region comprising (i) a first peptide linker that does not comprise an amino acid sequence comprising a secondary structure of an alpha helix or beta strand, and (ii) a first therapeutic agent; 1 a first immunoglobulin fusion protein comprising a first antibody region attached to a non-antibody region; and (b) the extender fusion region comprises (i) a second peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a second therapeutic agent, wherein the extender fusion region is attached to the extender fusion region. a second immunoglobulin fusion protein comprising a second antibody region. In some embodiments, the first linker peptide is a linking peptide or part of a linking peptide. In some embodiments, the second linker peptide is a connecting peptide or part of a connecting peptide. The dual fusion antibody may further comprise one or more protease cleavage sites.

The dual fusion antibody comprises (a) a first extender fusion region comprising (i) a first peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a first therapeutic agent, wherein the first therapeutic agent comprises: 1 a first immunoglobulin fusion protein comprising a first antibody region attached to an extender fusion region; and (b) the non-antibody region comprises (i) a second peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta-strand secondary structure and (ii) a second therapeutic agent; a second immunoglobulin fusion protein comprising a second antibody region. In some embodiments, the first linker peptide is a linking peptide or part of a linking peptide. In some embodiments, the second linker peptide is a connecting peptide or part of a connecting peptide. The dual fusion antibody may further comprise one or more protease cleavage sites.

The dual fusion antibody comprises (a) a first extender fusion region comprising (i) a first peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a first therapeutic agent, wherein the first therapeutic agent comprises: 1 a first immunoglobulin fusion protein comprising a first antibody region attached to an extender fusion region; and (b) the second extender fusion region comprises (i) a second peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a second therapeutic agent, wherein the second extender fusion region comprises: and a second immunoglobulin fusion protein comprising a second antibody region attached to the region. In some embodiments, the first linker peptide is a linking peptide or part of a linking peptide. In some embodiments, the second linker peptide is a connecting peptide or part of a connecting peptide. The dual fusion antibody may further comprise one or more protease cleavage sites.

A dual fusion antibody comprises (a) a first non-antibody region comprising (i) a first peptide linker that does not comprise an amino acid sequence comprising a secondary structure of an alpha helix or beta strand, and (ii) a first therapeutic agent; 1 a first immunoglobulin fusion protein comprising a first antibody region attached to a non-antibody region; and (b) the second non-antibody region comprises (i) an extender peptide comprising at least one or more secondary structures and (ii) a second therapeutic agent, wherein the second non-antibody region comprises a second antibody region attached to the second non-antibody region. and a second immunoglobulin fusion protein. In some embodiments, the extender peptide comprises an amino acid having an alpha helix secondary structure. In some embodiments, the extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the peptide linker is a linking peptide or part of a linking peptide. The dual fusion antibody may further comprise one or more protease cleavage sites. The dual fusion antibody may further comprise one or more additional linkers. The second non-antibody region of the second immunoglobulin fusion protein may further comprise one or more additional extender peptides.

A dual fusion antibody comprises (a) a first non-antibody region comprising (i) a first peptide linker that does not comprise an amino acid sequence comprising a secondary structure of an alpha helix or beta strand, and (ii) a first therapeutic agent; 1 a first immunoglobulin fusion protein comprising a first antibody region attached to a non-antibody region; and (b) a second immunoglobulin wherein the extender fusion region comprises (i) an extender peptide comprising at least one secondary structure and (ii) a second therapeutic agent, and wherein the second antibody region is attached to the extender fusion region. fusion proteins. In some embodiments, the extender peptide comprises an amino acid having an alpha helix secondary structure. In some embodiments, the extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the peptide linker is a linking peptide or part of a linking peptide. The dual fusion antibody may further comprise one or more protease cleavage sites. The dual fusion antibody may further comprise one or more additional linkers. The extender fusion region of the second immunoglobulin fusion protein may further comprise one or more additional extender peptides.

The dual fusion antibody comprises (a) a first extender fusion region comprising (i) a first peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a first therapeutic agent, wherein the first therapeutic agent comprises: 1 a first immunoglobulin fusion protein comprising a first antibody region attached to an extender fusion region; and (b) a second immunoglobulin wherein the non-antibody region comprises (i) an extender peptide comprising at least one secondary structure and (ii) a second therapeutic agent, wherein the second antibody region is attached to the non-antibody region. fusion proteins. In some embodiments, the extender peptide comprises an amino acid having an alpha helix secondary structure. In some embodiments, the extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the peptide linker is a linking peptide or part of a linking peptide. The dual fusion antibody may further comprise one or more protease cleavage sites. The dual fusion antibody may further comprise one or more additional linkers. The non-antibody region of the second immunoglobulin fusion protein may further comprise one or more additional extender peptides.

The dual fusion antibody comprises (a) a first extender fusion region comprising (i) a first peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a first therapeutic agent, wherein the first therapeutic agent comprises: 1 a first immunoglobulin fusion protein comprising a first antibody region attached to an extender fusion region; and (b) a second extender fusion region comprising (i) an extender peptide comprising at least one secondary structure and (ii) a second antibody region attached to the second extender fusion region, wherein the second therapeutic agent is attached to the second extender fusion region. a second immunoglobulin fusion protein. In some embodiments, the extender peptide comprises an amino acid having an alpha helix secondary structure. In some embodiments, the extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the peptide linker is a linking peptide or part of a linking peptide. The dual fusion antibody may further comprise one or more protease cleavage sites. The dual fusion antibody may further comprise one or more additional linkers. The second extender fusion region of the second immunoglobulin fusion protein may further comprise one or more additional extender peptides.

The dual fusion antibody comprises (a) a first non-antibody region comprising (i) a first extender peptide comprising an amino acid sequence comprising a secondary structure of an alpha helix and (ii) a first therapeutic agent, said first non-antibody region a first immunoglobulin fusion protein comprising a first antibody region attached to; and (b) the second non-antibody region comprises (i) a peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta-strand secondary structure and (ii) a second therapeutic agent; and a second immunoglobulin fusion protein comprising an attached second antibody region. In some embodiments, the extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the peptide linker is a linking peptide or part of a linking peptide. The dual fusion antibody may further comprise one or more protease cleavage sites. The dual fusion antibody may further comprise one or more additional linkers. The first non-antibody region of the first immunoglobulin fusion protein may further comprise one or more additional extender peptides.

The dual fusion antibody comprises (a) a first non-antibody region comprising (i) a first extender peptide comprising an amino acid sequence comprising a secondary structure of an alpha helix and (ii) a first therapeutic agent, said first non-antibody region a first immunoglobulin fusion protein comprising a first antibody region attached to; and (b) the extender fusion region comprises (i) a second peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a second therapeutic agent, wherein the extender fusion region is attached to the extender fusion region. a second immunoglobulin fusion protein comprising a second antibody region. In some embodiments, the extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the peptide linker is a linking peptide or part of a linking peptide. The dual fusion antibody may further comprise one or more protease cleavage sites. The dual fusion antibody may further comprise one or more additional linkers. The first non-antibody region of the first immunoglobulin fusion protein may further comprise one or more additional extender peptides.

The dual fusion antibody comprises (a) a first extender fusion region comprising (i) a first extender peptide comprising an amino acid sequence comprising a secondary structure of an alpha helix and (ii) a first therapeutic agent, wherein the first extender fusion region comprises: a first immunoglobulin fusion protein comprising a first antibody region attached to; and (b) the non-antibody region comprises (i) a peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a second therapeutic agent; a second immunoglobulin fusion protein comprising an antibody region. In some embodiments, the extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the peptide linker is a linking peptide or part of a linking peptide. The dual fusion antibody may further comprise one or more protease cleavage sites. The dual fusion antibody may further comprise one or more additional linkers. The first extender fusion region of the first immunoglobulin fusion protein may further comprise one or more additional extender peptides.

The dual fusion antibody comprises (a) a first extender fusion region comprising (i) a first extender peptide comprising an amino acid sequence comprising a secondary structure of an alpha helix and (ii) a first therapeutic agent, wherein the first extender fusion region comprises: a first immunoglobulin fusion protein comprising a first antibody region attached to; and (b) the second extender fusion region comprises (i) a peptide linker that does not comprise an amino acid sequence comprising an alpha helix or beta strand secondary structure and (ii) a second therapeutic agent, wherein the second extender fusion region comprises: and a second immunoglobulin fusion protein comprising an attached second antibody region. In some embodiments, the extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the extender peptide is a linking peptide or part of a linking peptide. In some embodiments, the peptide linker is a linking peptide or part of a linking peptide. The dual fusion antibody may further comprise one or more protease cleavage sites. The dual fusion antibody may further comprise one or more additional linkers. The first extender fusion region of the first immunoglobulin fusion protein may further comprise one or more additional extender peptides.

The first therapeutic agent and the second therapeutic agent may be the same. The first therapeutic agent and the second therapeutic agent may be different. The immunoglobulin dual fusion protein may further comprise one or more additional therapeutic agents. The two or more therapeutic agents may be the same. Alternatively, or additionally, the two or more therapeutic agents may be different. The first therapeutic agent may be a therapeutic peptide. The second therapeutic agent may be a therapeutic peptide. One or more of the additional therapeutic agents may be a therapeutic peptide. The first therapeutic agent may comprise a therapeutic peptide. The second therapeutic agent may comprise a therapeutic peptide. One or more of the additional therapeutic agents may comprise one or more therapeutic peptides. A therapeutic agent may comprise one or more therapeutic peptides or regions of therapeutic peptides. The therapeutic agent may include, for example, a first therapeutic peptide or portion thereof, an internal peptide, and a second therapeutic peptide or portion thereof. The internal peptide may include, for example, a protease cleavage site or an affinity tag, such as a histidine tag (6X HIS) (SEQ ID NO: 274). An internal peptide may include, for example, another therapeutic peptide or a portion thereof. For example, the therapeutic agent may comprise a first portion of a first therapeutic peptide, a first portion of a second therapeutic peptide, and a second portion of the first therapeutic peptide.

The first antibody region and the second antibody region may be identical. For example, the first antibody region and the second antibody region comprise an immunoglobulin heavy chain. Alternatively, the first antibody region and the second antibody region may comprise an immunoglobulin light chain. The first antibody region and the second antibody region may be different. For example, the first antibody region comprises an immunoglobulin heavy chain and the second antibody region comprises an immunoglobulin light chain, or vice versa. The immunoglobulin dual fusion protein may further comprise one or more additional antibody regions. The two or more antibody regions may be identical. Alternatively, or additionally, two or more antibody regions may be different.

The immunoglobulin dual fusion protein may further comprise one or more extender peptides. One or more extender peptides may be the same. Alternatively, or additionally, one or more extender peptides are different. In some embodiments, the extender peptide comprises 7 or fewer amino acids that are based on or derived from a very long CDR3.

The immunoglobulin dual fusion protein may further comprise one or more additional antibody regions. The two or more antibody regions may be identical. Alternatively, or additionally, the two or more antibody regions are different.

The immunoglobulin double fusion protein may further comprise one or more linkers. The immunoglobulin double fusion protein may further comprise two or more linkers. The two or more linkers may be the same. Alternatively, or additionally, the two or more linkers are different.

The immunoglobulin dual fusion protein may further comprise one or more proteolytic cleavage sites. The immunoglobulin dual fusion protein may further comprise two or more proteolytic cleavage sites. The two or more proteolytic cleavage sites may be identical. Alternatively, or additionally, the two or more proteolytic cleavage sites are different.

The immunoglobulin dual fusion protein may further comprise one or more therapeutic agents comprising an internal peptide. The internal peptide may comprise an affinity tag or label, eg, a HHHHHH(6X) histidine tag (SEQ ID NO: 274). The internal peptide may comprise a portion of a therapeutic peptide.

Representative immunoglobulin double fusion proteins are shown in Formula IIIA and Formula VIIA in FIG. 3 . As shown in Formula IIIA of FIG. 8 , the immunoglobulin dual fusion protein is (a) a first extender fusion region comprising a first therapeutic agent (T ¹ ) attached to two extender peptides (E ¹ , E ² ) a first antibody region attached to (A ¹ ); and (b) a second antibody region (A ² ) attached to a second extender fusion region comprising a second therapeutic agent (T ² ) attached to the two extender peptides (E ³ , E ⁴ ). The immunoglobulin fusion protein may further comprise one or more linkers and one or more proteolytic cleavage sites. One or more proteolytic cleavage sites may be attached to the N- and/or C-terminus of the therapeutic agent. Proteolytic cleavage of the proteolytic cleavage site can liberate the N- and/or C-terminus of the therapeutic agent from the immunoglobulin fusion protein. Formula VIIA of FIG. 3 shows a representative immunoglobulin double fusion protein in which the N-terminus of the second therapeutic agent (T ² ) is released.

antibody region

The immunoglobulin fusion proteins disclosed herein comprise one or more antibody regions. The antibody region may comprise an immunoglobulin or fragment thereof. The antibody region may comprise at least a portion of an immunoglobulin heavy chain, an immunoglobulin light chain, or a combination thereof. The antibody region may comprise two or more immunoglobulin chains or portions thereof. The antibody region may comprise three or more immunoglobulin chains or portions thereof. The antibody region may comprise four or more immunoglobulin chains or portions thereof. The antibody region may comprise five or more immunoglobulin chains or portions thereof. The antibody region may comprise two immunoglobulin heavy chains and two immunoglobulin light chains.

Antibody regions can include any polypeptide, including whole immunoglobulin molecules or fragments of immunoglobulins, heavy chains, light chains, variable domains, constant domains, complementarity determining regions (CDRs), framework regions, fragment antigen binding (Fab) ) region, Fab', F(ab')2, F(ab')3, Fab', fragment crystallization (Fc) region, single chain variable fragment (scFV), di-scFv, single domain immunoglobulin, trifunctional immunoglobulin , chemically linked F(ab′) 2 , and any combination thereof. The immunoglobulin region may comprise one or more mutations. The Fc region may be a mutated Fc region. The mutated Fc region may contain one or more mutations that eliminate the antibody-dependent cellular cytotoxicity (ADCC) effect of the Fc region. The mutated Fc region is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 to about 10, about 1 to about 20, or about 1 to about 30 mutations.

In some embodiments, an immunoglobulin heavy chain may comprise an entire heavy chain or a portion of a heavy chain. For example, a variable domain derived from a heavy chain or a region thereof may be referred to as a heavy chain or heavy chain region. In some embodiments, an immunoglobulin light chain may comprise an entire light chain or a portion of a light chain. For example, a variable domain derived from a light chain or a region thereof may be referred to as a light chain or light chain region. Single domain immunoglobulins include, but are not limited to, single monomeric variable immunoglobulin domains such as shark variable novel antigen receptor immunoglobulin fragments (VNARs).

Immunoglobulins may be derived from any form known to those of skill in the art, including, but not limited to, IgA, IgD, IgE, IgG, IgM, IgY, IgW. An antibody region may comprise more than one unit, including but not limited to 1, 2, 3, 4, and 5 units. The functional units are non-antibody regions, heavy chains, light chains, variable domains, constant domains, complementarity determining regions (CDRs), framework regions, fragment antigen binding (Fab) regions, Fab', F(ab')2, F(ab') ) 3, Fab', fragment crystallization (Fc) region, single chain variable fragment (scFV), di-scFv, single domain immunoglobulin, trifunctional immunoglobulin, chemically linked F(ab')2, and any combination thereof including but not limited to. Non-antibody regions include, but are not limited to, carbohydrates, lipids and small molecules and therapeutic peptides. An antibody region may comprise one or more units linked by one or more disulfide bonds. The antibody region may comprise one or more units linked by a peptide linker, eg, scFv immunoglobulin. The immunoglobulin may be a recombinant immunoglobulin, including an immunoglobulin having amino acid mutations, substitutions and/or deletions. The immunoglobulin may be a recombinant immunoglobulin comprising chemical modifications. An immunoglobulin may comprise all or part of an immunoglobulin-drug conjugate.

The antibody region may comprise at least a portion of an immunoglobulin heavy chain. The antibody region may comprise one or more immunoglobulin heavy chains or portions thereof. The antibody region may comprise two or more immunoglobulin heavy chains or portions thereof. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to an immunoglobulin heavy chain. The antibody region may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to an immunoglobulin heavy chain. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to an immunoglobulin heavy chain. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to an immunoglobulin heavy chain. The antibody region may comprise an amino acid sequence that is at least about 90% homologous to an immunoglobulin heavy chain. The immunoglobulin heavy chain may comprise amino acids based on or derived from any one of SEQ ID NOs: 22-27, and 29-35. In some embodiments, the antibody region comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, and an amino acid sequence that is 90%, 95%, or 97% homologous. In some embodiments, the antibody region is at least about 50%, 55%, 60% to the amino acid sequence of any one of SEQ ID NOs: 22-27 and 29-35 %, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical amino acid sequence;

The antibody region may comprise an amino acid sequence comprising 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or more amino acids of an immunoglobulin heavy chain. The antibody region may comprise an amino acid sequence comprising 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or more amino acids of an immunoglobulin heavy chain. The amino acids may be contiguous. Alternatively, or additionally, the amino acids are discontinuous.

The immunoglobulin heavy chain may be encoded by a nucleotide sequence based on or derived from SEQ ID NOs: 4-9, and 11-17. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 50% homologous to SEQ ID NOs: 4-9, and 11-17. wherein the immunoglobulin heavy chain is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to SEQ ID NOs: 4-9, and 11-17. It may be encoded by a nucleotide sequence. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 75% homologous to SEQ ID NOs: 4-9, and 11-17. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 85% homologous to SEQ ID NOs: 4-9, and 11-17. In some embodiments, the antibody region comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, It is encoded by a nucleotide sequence that is 90%, 95%, or 97% homologous. In some embodiments, the antibody region comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, It is encoded by a nucleotide sequence that is 90%, 95%, or 97% identical.

The antibody region may comprise at least a portion of an immunoglobulin light chain. The antibody region may comprise one or more immunoglobulin light chains or portions thereof. The antibody region may comprise two or more immunoglobulin light chains or portions thereof. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to an immunoglobulin light chain. The antibody region may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to an immunoglobulin light chain. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to an immunoglobulin light chain. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to an immunoglobulin light chain. The antibody region may comprise an amino acid sequence that is at least about 90% homologous to an immunoglobulin light chain. The immunoglobulin light chain may comprise an amino acid sequence based on or derived from any one of SEQ ID NOs: 19-21, 28, and 36. In some embodiments, the antibody region comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% of the amino acid sequence of any one of SEQ ID NOs: 19-21, 28, and 36. , an amino acid sequence that is 90%, 95%, or 97% homologous. In some embodiments, the antibody region comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% of the amino acid sequence of any one of SEQ ID NOs: 19-21, 28, and 36. , 90%, 95%, or 97% identical amino acid sequence.

The antibody region may comprise an amino acid sequence comprising 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or more amino acids of an immunoglobulin light chain. The antibody region may comprise an amino acid sequence comprising 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or more amino acids of an immunoglobulin light chain. The amino acids may be contiguous. Alternatively, or additionally, the amino acids are discontinuous.

The immunoglobulin light chain may be encoded by a nucleotide sequence based on or derived from SEQ ID NOs: 1-3, 10, and 18. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 50% homologous to SEQ ID NOs: 1-3, 10, and 18. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 75% homologous to SEQ ID NOs: 1-3, 10, and 18. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 85% homologous to SEQ ID NOs: 1-3, 10, and 18. In some embodiments, the antibody region comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, It can be encoded by a nucleotide sequence that is 90%, 95%, or 97% homologous. In some embodiments, the antibody region comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, It can be encoded by a nucleotide sequence that is 90%, 95%, or 97% identical.

An antibody region may comprise at least a portion of a variable domain. An antibody region may comprise one or more variable domains or portions thereof. An antibody region may comprise 2, 3, 4, 5 or more variable domains or portions thereof. An antibody region may be based on or derived from the amino acid sequence of one or more variable domains 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 225, 250 , 275, 300, 350, 400, an amino acid sequence comprising 500 or more amino acids. The amino acids may be contiguous. The amino acids may be discontinuous.

An antibody region may comprise at least a portion of a constant domain. An antibody region may comprise one or more constant domains or portions thereof. An antibody region may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more constant domains or portions thereof. An antibody region may be based on or derived from the amino acid sequence of one or more constant domains 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 225, 250 , 275, 300, 350, 400, 500, 600, 700, 800, 900, 1000, 1200, 1400 or more amino acids. The amino acids may be contiguous. The amino acids may be discontinuous.

The antibody region may comprise at least a portion of a complementarity determining region (CDR). An antibody region may comprise one or more complementarity determining regions (CDRs) or portions thereof. An antibody region may comprise 2, 3, 4, 5 or more complementarity determining regions (CDRs) or portions thereof. The antibody region may comprise 6, 7, 8 or more complementarity determining regions (CDRs) or portions thereof. An antibody region may comprise four or more complementarity determining regions (CDRs) or portions thereof. The antibody region may comprise 9, 10, 11 or more complementarity determining regions (CDRs) or portions thereof. The one or more CDRs may be CDR1, CDR2, CDR3, or a combination thereof. The one or more CDRs may be CDR1. The one or more CDRs may be CDR2. The one or more CDRs may be CDR3. The CDR may be a heavy chain CDR. The one or more CDRs may be a light chain CDR.

The antibody region may comprise an amino acid sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids based on or derived from the amino acid sequence of a CDR. An antibody region may comprise an amino acid sequence comprising three or more amino acids based on or derived from the amino acid sequence of a CDR. An antibody region may comprise an amino acid sequence comprising 5 or more amino acids based on or derived from the amino acid sequence of a CDR. An antibody region may comprise an amino acid sequence comprising 10 or more amino acids based on or derived from the amino acid sequence of a CDR. The amino acids may be contiguous. The amino acids may be discontinuous.

The antibody region may be based on or derived from at least a portion of an anti-T cell receptor immunoglobulin. The antibody region may be based on or derived from at least a portion of an anti-B cell receptor immunoglobulin.

The antibody region may be based on or derived from at least a portion of an anti-T cell co-receptor immunoglobulin. The antibody region may be based on or derived from at least a portion of an anti-CD3 immunoglobulin. The antibody region may be based on or derived from an anti-CD3 immunoglobulin. The anti-CD3 immunoglobulin may be UCHT1. The antibody region may be based on or derived from at least a portion of a Fab fragment of an anti-CD3 immunoglobulin. The antibody region may be based on or derived from an immunoglobulin fragment of an anti-CD3 immunoglobulin.

The antibody region may be based on or derived from an immunoglobulin or immunoglobulin fragment that binds to at least a portion of a receptor on a cell. The antibody region may be based on or derived from an immunoglobulin or immunoglobulin fragment that binds to at least a portion of a coreceptor on a cell. The antibody region may be based on or derived from an immunoglobulin or immunoglobulin fragment that binds to at least a portion of an antigen or cell surface marker on a cell. The cell may be a hematopoietic cell. The hematopoietic cell may be a bone marrow cell. The bone marrow cells may be red blood cells, platelets, neutrophils, monocytes, macrophages, eosinophils, basophils, or mast cells. The hematopoietic cell may be a lymphoid cell. The lymphoid cells may be B cells, T cells, or NK cells. The hematopoietic cell may be a white blood cell. The hematopoietic cell may be a lymphocyte.

The antibody region may be based on or derived from an immunoglobulin or immunoglobulin fragment that binds to at least a portion of a receptor on a T cell. The receptor may be a T-cell receptor (TCR). The TCR may comprise TCR alpha, TCR beta, TCR gamma and/or TCR delta. The receptor may be a T cell receptor zeta.

The antibody region may be based on or derived from an immunoglobulin or immunoglobulin fragment that binds to at least a portion of a receptor on a lymphocyte, B cell, macrophage, monocyte, neutrophil and/or NK cell. The receptor may be an Fc receptor. The Fc receptor may be an Fc-gamma receptor, an Fc-alpha receptor and/or an Fc-epsilon receptor. Fc-gamma receptors include, but are not limited to, FcγRI (CD64), FcγRIIA (CD32), FcγRIIB (CD32), FcγRIIIA (CD16a) and FcγRIIIB (CD16b). Fc-alpha receptors include, but are not limited to, FcαRI. Fc-epsilon receptors include, but are not limited to, FcεRI and FcεRII. The receptor may be CD89 (IgA receptor or Fc fragment of FCAR).

The antibody region may be based on or derived from an immunoglobulin or immunoglobulin fragment that binds to at least a portion of a coreceptor on a T cell. The co-receptor may be CD3, CD4, and/or CD8. The antibody region may be based on or derived from an immunoglobulin fragment that binds to the CD3 co-receptor. The CD3 co-receptor may comprise CD3-gamma, CD3-delta and/or CD3-epsilon. CD8 may comprise CD8-alpha and/or CD8-beta chains.

In some embodiments, the antibody region is not specific for a mammalian target. In some embodiments, the immunoglobulin is an antiviral immunoglobulin. In some embodiments, the immunoglobulin is an antibacterial immunoglobulin. In some embodiments, the immunoglobulin is an antiparasitic immunoglobulin. In some embodiments, the immunoglobulin is an antifungal immunoglobulin. In some embodiments, the antibody region is derived from an immunoglobulin vaccine.

In some embodiments, the antibody region comprises: actoxumab, bezlotoxumab, CR6261, edovacomab, efungumab, exbivirumab, felbizumab, foravirumab, ivalizumab (TMB-355, TNX-355); Ribivirumab, Motabizumab, Nebacumab, Fazibaximab, Palivizumab, Panobacumab, Rafivirumab, Laxibacumab, Regavirumab, Sevirumab (MSL-109), Subizumab, Tefiva Based on or derived from immunoglobulins including, but not limited to, zumab, tuvirumab, and ultoxazumab.

In some embodiments, the antibody region is a Clostridium difficile, orthomyxovirus (influenzavirus A, influenzavirus B, influenzavirus C, Isavirus, Thogotovirus), escheri Escherichia coli, Candida, rabies, human immunodeficiency virus, hepatitis, staphylococcus, respiratory syncytial virus, Pseudomonas aeruginosa, Bacillus anthracis, cytomegalovirus, or staphylo Based on or derived from immunoglobulins targeting Staphylococcus aureus.

The antibody region may be based on or derived from an antiviral immunoglobulin. Antiviral immunoglobulins can be directed against epitopes of viral proteins. Antibacterial immunoglobulins include, but are not limited to, adenoviruses, herpesviruses, poxviruses, parvoviruses, reoviruses, picornaviruses, togaviruses, ordomixoviruses, ravdoviruses, retroviruses and hepadnaviruses. However, it can target more than one virus. The viral protein may be derived from a respiratory syncytial virus. The viral protein may be an F protein of a respiratory syncytial virus. The epitope may be the A antigenic site of the F protein. The antiviral immunoglobulin may be based on or derived from palivizumab. The immunoglobulin may be based on or derived from an antiviral vaccine. Antiviral immunoglobulins include exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab may be based on or derived from.

The antibody region may be based on or derived from antiviral immunoglobulin G. The antibody region may comprise at least a portion of an antiviral immunoglobulin G. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of an antiviral immunoglobulin G. The antibody region comprises an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to at least a portion of an antiviral immunoglobulin G. may include The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of an antiviral immunoglobulin G. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of an antiviral immunoglobulin G. In some embodiments the antibody region comprises an amino acid sequence based on or derived from antiviral immunoglobulin M.

The antibody region may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of an antiviral immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of an antiviral immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 50 or more amino acids of an antiviral immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 100 or more amino acids of an antiviral immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising at least 200 amino acids of an antiviral immunoglobulin G sequence.

The antibody region may be based on or derived from palivizumab immunoglobulin. The antibody region may comprise at least a portion of a palivizumab immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of a palivizumab immunoglobulin. The antibody region comprises an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to at least a portion of a palivizumab immunoglobulin. may include The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of a palivizumab immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of a palivizumab immunoglobulin.

The antibody region may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of a palivizumab immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of a palivizumab immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 50 or more amino acids of a palivizumab immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising at least 100 amino acids of a palivizumab immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 200 or more amino acids of a palivizumab immunoglobulin sequence.

The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. may be based on or derived from. The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. may include at least a portion of The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. an amino acid sequence that is at least about 50% homologous to at least a portion of The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to at least a portion of The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. an amino acid sequence that is at least about 70% homologous to at least a portion of The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. an amino acid sequence that is at least about 80% homologous to at least a portion of

The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of the sequence. The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. an amino acid sequence comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of the sequence. The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. an amino acid sequence comprising 50 or more amino acids of the sequence. The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. an amino acid sequence comprising 100 or more amino acids of the sequence. The antibody region comprises exbivirumab, foravirumab, ribivirumab, rafivirumab, regavirumab, cevirumab, tuvirumab, felbizumab, motavizumab, palivizumab, and/or suvizumab immunoglobulin. an amino acid sequence comprising 200 or more amino acids of the sequence.

The antibody region may be based on or derived from an antimicrobial immunoglobulin. Antimicrobial immunoglobulins can be directed against epitopes of bacterial proteins. Antibacterial immunoglobulin Acetobacter orantius aurantius ), Agrobacterium radiobacter ( Agrobacterium radiobacter ), Anaplasma phagocytophilum ) , Azorhizobium caulinodans ), Bacillus anthracis, Bacillus brevis ( Bacillus brevis ) Bacillus cereus ), Bacillus subtilis ( Bacillus subtilis ), Bacteroides fragilis ( Bcteroides fragilis ), Bacteroides gingivalis ( Bcteroides gingivalis ), Bacteroides melaninoidus ( Bcteroides ) melaninogenicus ), Bartonella quintana quintana ), Bordetella bronchiseptica ), Bordetella pertussis , Borrelia burgdorferi , Brucella abortus ), Brucella melitensis ( melitensis ), Brucella suis ( Brucella suis ), Burkholderia malaysia ( Burkholderia ) mallei ), Burkholderia pseudomallei , Burkholderia sepasia ( Burkholderia ) cepacia ), Kalymmatobacterium granulomatis ( Calymmatobacterium granulomatis ), Campylobacter coli , Campylobacter fetus , Campylobacter jejuni , Campylobacter pylori , Chlamydia trachomatis Midophila pneumoniae ( Chlamydophila pneumoniae ), Chlamydophila psittaci ), Clostridium botulinum ( Clostridium botulinum ), Clostridium difficile, Corynebacterium diphtheriae ( Corynebacterium diphtheriae ), Corynebacterium fujiforme ( Corynebacterium ) fusiforme ), Coxiella burnetii ), Enterobacter cloake ( Enterobacter cloacae ), Enterococcus faecalis , Enterococcus faecalis ) faecium ), Enterococcus galllinarum ( Enterococcus galllinarum ), Enterococcus malolatus ( Enterococcus maloratus ), Escherichia coli, Francisella tularensis ), Fusobacterium nucleatum ( Fusobacterium nucleatum ), Gardnerella vaginalis ( Gardnerella ) vaginalis ) , Haemophilus influenzae influenzae ), Haemophilus parainfluenzae , Haemophilus pertussis ( Haemophilus ) pertussis ), Haemophilus vaginalis ( Haemophilus ) vaginalis ), Helicobacter pylori , Klebsiella pneumoniae pneumoniae ), Lactobacillus acidophilus ( Lactobacillus acidophilus ), Lactococcus lactis ( Lactococcus ) lactis ), Legionella pneumophila ( Legionella ) pneumophila ), Listeria monocytogenes ( Listeria monocytogenes ), Methanobacterium extrokens ( Methanobacterium ) extroquens ), Microbacterium multiforme ( Microbacterium multiforme ), Micrococcus luteus ( Micrococcus luteus ), Moraxella catarrhalis ( Moraxella ) catarrhalis ), Mycobacterium play ( Mycobacterium phlei ), Mycobacterium smegmatis ), Mycobacterium tuberculosis ( Mycobacterium tuberculosis ), Mycoplasma genitalium ( Mycoplasma ) genitalium ), Mycoplasma hominis ( Mycoplasma hominis ), Mycoplasma pneumoniae ( Mycoplasma pneumonie ), Neisseria gonorrhoeae , Neisseria meningitidis ( Neisseria ) meningitidis ), Pasteurella multocida ), Pasteurella tularensis ), Peptostreptococcus , Porphyromonas gingivalis ) melaninogenica ), Pseudomonas aeruginosa, Rhizobium radiobacter radiobacter ), Rickettsia rickettsii ), Rothia dentocariosa ( Rothia ) dentocariosa ), Salmonella enteritidis ( Salmonella enteritidis ), Salmonella typhi ( Salmonella typhi ), Salmonella typhimurium ( Salmonella typhimurium ), Shigella descentie ( Shigella ) dysenteriae ), Staphylococcus aureus , Staphylococcus epidermidis , Stenotrophomonas maltophilia , Streptococcus pneumoniae, Streptococcus pneumoniae , Streptococcus pneumoniae Pyyogenes ( Streptococcus pyogenes ), Treponema pallidum ( Treponema pallidum ), Treponema denticola ( Treponema ) denticola ), Vibrio cholera ( Vibrio ) cholerae ), Vibrio comma ( Vibrio comma ), Vibrio parahaemolyticus ( Vibrio parahaemolyticus ), Vibrio vulnipicus ( Vibrio ) vulnificus ) , Yersinia enterocolica enterocolitica ) and Yersinia pseudotuberculosis ). The immunoglobulin may be based on or derived from a bacterial vaccine. The antiviral immunoglobulin may be based on or derived from nebacumab, panobacumab, laxibacumab, edovacomab, phazivacimab, and/or tefivazumab.

The antibody region may be based on or derived from an antimicrobial immunoglobulin G. The antibody region may comprise at least a portion of an antimicrobial immunoglobulin G. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of an antimicrobial immunoglobulin G. The antibody region comprises an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to at least a portion of an antimicrobial immunoglobulin G. can do. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of an antimicrobial immunoglobulin G. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of an antimicrobial immunoglobulin G. In some embodiments the antibody region comprises an aminosa sequence based on or derived from antiviral immunoglobulin M.

The antibody region may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of an antimicrobial immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of an antimicrobial immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 50 or more amino acids of an antimicrobial immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 100 or more amino acids of an antimicrobial immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising at least 200 amino acids of an antimicrobial immunoglobulin G sequence.

The antibody region may be based on or derived from nebacumab, panovacumab, laxibacumab, edovacomab, phagebaximab, and/or tefivazumab immunoglobulins. The antibody region may comprise at least a portion of a nebacumab, panovacumab, laxibacumab, edovacomab, phazibaximab, and/or tefivazumab immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of a nebacumab, panovacumab, laxibacumab, edovacomab, phazibaximab, and/or tefivazumab immunoglobulin. The antibody region comprises at least a portion and at least about 60%, 65%, 70%, 75%, 80 amino acid sequences that are at least %, 85%, 90%, 92%, 95%, or 97% homologous. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of a nebacumab, panovacumab, laxibacumab, edovacomab, phazibaximab, and/or tefivazumab immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of a nebacumab, panovacumab, laxibacumab, edovacomab, phazibaximab, and/or tefivazumab immunoglobulin.

The antibody regions are 10, 20, 30, 40, 50, 60, 70, 80, 90 of the nebacumab, panovacumab, laxibacumab, edovacomab, phagebaximab, and/or tefivazumab immunoglobulin sequences. It may comprise an amino acid sequence comprising more than one amino acid. The antibody region may be 100, 200, 300, 400, 500, 600, 700, 800, 900 of the nebacumab, panovacumab, laxibacumab, edovacomab, phazibaximab, and/or tefivazumab immunoglobulin sequences. It may comprise an amino acid sequence comprising more than one amino acid. The antibody region may comprise an amino acid sequence comprising at least 50 amino acids of a nebacumab, panovacumab, laxibacumab, edovacomab, phagebaximab, and/or tefivazumab immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising at least 100 amino acids of a nebacumab, panovacumab, laxibacumab, edovacomab, phagevacimab, and/or tefivazumab immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 200 or more amino acids of a nebacumab, panovacumab, laxibacumab, edovacomab, phazibaximab, and/or tefivazumab immunoglobulin sequence.

The antibody region may be based on or derived from an antiparasitic immunoglobulin. Antiparasitic immunoglobulins can be directed against parasitic proteins. Antiparasitic immunoglobulins are parasites Acanthamoeba, Balamuthia mandrillaris, Babesia (B. divergens), B. bigemina (B. bigemina) , B. equi, B. microfti, B. duncani), Balantidium coli, Blastocystis, Cryptosporidium (Cryptosporidium), Dientamoeba fragilis, Entamoeba histolytica, Giardia lamblia, Isospora belli, Leishmania, yes Naegleria fowleri, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, 4 ovale wallikeri Plasmodium malariae, Plasmodium knowlesi, Rhinosporidium seeberi, Sarcocystis bovihominis, Sarcocystis suihominis, Sarcocystis suihominis Toxoplasma gondii, Trichomonas vaginalis, Trypanosoma brucei, Trypanosoma cruzi, Cestoda, Taenia multiceps, Diphyllobothrium ), Echinococcus granulosa Echinococcus granulosus, Echinococcus multilocularis, Echinococcus vogeli, Echinococcus oligarpithrus, Hymenolepis nana, diminuta), Taenia saginata, Taenia solium, Bertiella mucronata, Bertiella studeri, Tapeworm (Spirometra erinaceieuropaei), Liver fluke (Clonorchis); Clonorchis viverrini, Dicrocoelium dendriticum, Fasciola hepatica, Fasciola gigantica, Fasciolopsis buski, Gnathostoma spinigerum, Gnathostoma hispidum, Gnathostoma hispidum Yokogawa fluke (Metagonimus yokogawai), Taigan fluke (Opisthorchis viverrini), Cat liver fluke (Opisthorchis felineus), liver fluke (Clonorchis sinensis), Westman lung fluke (Paragonimus westermani); African lung fluke (Paragonimus africanus); Lung fluke caliensis species (Paragonimus caliensis); Lung fluke Kellicotti (Paragonimus kellicotti); Lung fluke skrjabini species (Paragonimus skrjabini); Lung fluke Paragonimus uterobilateralis, Schistosoma sp., Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum Schistosoma mekongi), Echinostoma echinatum, Trichobilharzia regenti, Schistosomatidae, Ancylostoma duodenale, American hookworm (Neciosgylus americanus), costaricensis), Anisakis, Ascaris sp., Human roundworm (Ascaris lumbricoides), Raccoon roundworm (Baylisascaris procyonis), Malayan filamentous insect (Brugia malayi), thymol filamentous insect (Brugia timori), Newworm (Dioctophyme renale) Nematode (Dracunculus medinensis), pinworm (Enterobius vermicularis), Enterobius gregorii (Enterobius gregorii), Halicephalobus gingivalis (Halicephalobus gingivalis), Loa filaria (Loa filaria), Mansonella streptocerca (Mansonella streptocerca) Onchocerca volvulus, Strongyloides stercoralis, California eyeworm (Thelazia californiensis), Oriental eyeworm (Thelazia callipaeda), Toxocara canis, Cat roundworm (Taxocara cati), Trichinella spiralis (Trichinella spiralis) ), Trichinella britovi, Trichinella nell Trichinella nelsoni, Trichinella nativa, Trichuris trichiura, Trichuris vulpis, Wuchereria bancrofti, Archiacanthocephala, Moniliformis monili Formis (Moniliformis moniliformis), tongue insect (Linguatula serrata), oestroidea (Oestroidea), black fly (Calliphoridae), ship fly (Sarcophagidae), sand flea (Tunga penidaetrans), human fly (Dermatobia hominis), tick (Ixodidae) , carp mite (Argasidae), bedbug (Cimex lectularius), lice (Pediculus humanus), body lice (Pediculus humanus corporis), pubic lice (Pthirus pubis), Demodex folliculorum/brevis/canis , Sarcoptes scabiei, Cochliomyia hominivorax, and human fleas (Pulex irritans).

The antibody region may be based on or derived from antiparasitic immunoglobulin G. The antibody region may comprise at least a portion of an antiparasitic immunoglobulin G. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of an antiparasitic immunoglobulin G. The antibody region comprises an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to at least a portion of an antiparasitic immunoglobulin G. may include The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of an antiparasitic immunoglobulin G. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of an antiparasitic immunoglobulin G. In some embodiments the antibody region comprises an amino acid sequence based on or derived from antiparasitic immunoglobulin M.

The antibody region may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of an antiparasitic immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of an antiparasitic immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 50 or more amino acids of an antiparasitic immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising at least 100 amino acids of an antiparasitic immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising at least 200 amino acids of an antiparasitic immunoglobulin G sequence.

The antibody region may be based on or derived from an antifungal immunoglobulin. Antimicrobial immunoglobulins can be directed against an epitope of a fungal protein. Antifungal immunoglobulins include Cryptococcus neoformans , Cryptococcus gattii , Candida albicans . albicans ), Candida tropicalis , Candida stellatoidea ( Candida ) stellatoidea , Candida glabrata glabrata ), Candida krusei ( Candida krusei ), Candida parapsilosis ( Candida ) parapsilosis ), Candida guilliermondii , Candida viswanati (C andida viswanathii ), Candida lusitaniae , Rhodotorula mucilaginosa ), Schizosaccharomyces pombe ), Saccharomyces cerevisiae , Brettanomyces bruxellensis , Candida stella stellata ), Schizoscharomyces pombe, Torulaspora delbruecki ( Torulaspora ) delbrueckii ), Zygosaccharomyces bailii , Yarrowia lipolytica lipolytica ), Saccharomyces exciguus ( Saccharomyces ) exiguus ) and Pichia pastoris ), including, but not limited to, fungal or fungal proteins. The antifungal immunoglobulin may be based on or derived from efungumab.

The antibody region may be based on or derived from antifungal immunoglobulin G. The antibody region may comprise at least a portion of an antifungal immunoglobulin G. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of an antifungal immunoglobulin G. The antibody region comprises an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to at least a portion of an antifungal immunoglobulin G. can do. The antibody region comprises an amino acid sequence that is at least about 70% homologous to at least a portion of an antifungal immunoglobulin G. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of an antifungal immunoglobulin G. In some embodiments the antibody region may comprise an amino acid sequence based on or derived from antifungal immunoglobulin M.

The antibody region may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of an antifungal immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of an antifungal immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 50 or more amino acids of an antifungal immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising 100 or more amino acids of an antifungal immunoglobulin G sequence. The antibody region may comprise an amino acid sequence comprising at least 200 amino acids of an antifungal immunoglobulin G sequence.

The antibody region may be based on or derived from an efungumab immunoglobulin. The antibody region may comprise at least a portion of an efungumab immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of an efungumab immunoglobulin. The antibody region comprises an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to at least a portion of an efungumab immunoglobulin. can do. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of an efungumab immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of an efungumab immunoglobulin.

The antibody region may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of an efungumab immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of an efungumab immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising at least 50 amino acids of an efungumab immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 100 or more amino acids of an efungumab immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 200 or more amino acids of an efungumab immunoglobulin sequence.

The antibody region may be based on or derived from trastuzumab immunoglobulin G immunoglobulin. The antibody region may comprise at least a portion of a trastuzumab immunoglobulin G immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of a trastuzumab immunoglobulin G immunoglobulin. The antibody region is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to at least a portion of a Trastuzumab immunoglobulin G immunoglobulin. It may comprise an amino acid sequence. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of a trastuzumab immunoglobulin G immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of a trastuzumab immunoglobulin G immunoglobulin. The antibody region may comprise a mutated trastuzumab antibody. The antibody region may comprise a trastuzumab antibody comprising seven mutations in an IgG1 heavy chain. The antibody region may comprise a trastuzumab antibody comprising three mutations in an IgG4 heavy chain.

The antibody region may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of a trastuzumab immunoglobulin G immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of a trastuzumab immunoglobulin G immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising at least 50 amino acids of a trastuzumab immunoglobulin G immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 100 or more amino acids of a trastuzumab immunoglobulin G immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising at least 200 amino acids of a trastuzumab immunoglobulin G immunoglobulin sequence.

The antibody region may be based on or derived from an anti-Her2 immunoglobulin. The antibody region may comprise at least a portion of an anti-Her2 immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of an anti-Her2 immunoglobulin. The antibody region comprises an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to at least a portion of an anti-Her2 immunoglobulin. may include The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of an anti-Her2 immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of an anti-Her2 immunoglobulin.

The antibody region may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of an anti-Her2 immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of an anti-Her2 immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 50 or more amino acids of an anti-Her2 immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 100 or more amino acids of an anti-Her2 immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 200 or more amino acids of an anti-Her2 immunoglobulin sequence.

The antibody region may be based on or derived from an anti-CD47 immunoglobulin. The antibody region may comprise at least a portion of an anti-CD47 immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of an anti-CD47 immunoglobulin. The antibody region comprises an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% homologous to at least a portion of an anti-CD47 immunoglobulin. may include The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of an anti-CD47 immunoglobulin. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of an anti-CD47 immunoglobulin.

The antibody region may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of an anti-CD47 immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of an anti-CD47 immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 50 or more amino acids of an anti-CD47 immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 100 or more amino acids of an anti-CD47 immunoglobulin sequence. The antibody region may comprise an amino acid sequence comprising 200 or more amino acids of an anti-CD47 immunoglobulin sequence.

The antibody region may be based on or derived from an anti-cancer immunoglobulin. Examples of anticancer immunoglobulins include absiximab, adalimumab, alemtuzumab, basiliximab, belimumab, bevacizumab, brentuximab, canakinumab, sertolizumab, cetuximab, daclizumab , denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab, infliximab, ipilimumab, muromonap-cd3, natalizumab, ofatumumab, omalizumab, pali bizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab, trastuzumab.

The antibody region may comprise at least a portion of a human immunoglobulin. The antibody region may comprise at least a portion of a humanized immunoglobulin. The antibody region may comprise at least a portion of a chimeric immunoglobulin. The antibody region may be based on or derived from a human immunoglobulin. The antibody region may be based on or derived from a humanized immunoglobulin. The antibody region may be based on or derived from a chimeric immunoglobulin. The antibody region may be based on or derived from a monoclonal immunoglobulin. The antibody region may be based on or derived from a polyclonal immunoglobulin. The antibody region may comprise at least a portion of an immunoglobulin derived from a mammal, avian, reptile, amphibian, or combination thereof. The mammal may be a human. The mammal may be a non-human primate. The mammal can be a dog, cat, sheep, goat, dairy cow, guinea pig or mouse.

The antibody region may comprise sequences based on or derived from one or more immunoglobulin and/or immunoglobulin fragment sequences. The antibody region comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% of a sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. , 92%, 95%, 97%, 98%, 99% or more homologous sequences. The antibody region may comprise a sequence that is at least about 70% homologous to a sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The antibody region may comprise a sequence that is at least about 80% homologous to a sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The antibody region may comprise a sequence that is at least about 90% homologous to a sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The antibody region may comprise a sequence that is at least about 95% homologous to a sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The sequence may be a peptide sequence. The sequence may be a nucleotide sequence.

The antibody region comprises a peptide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments and about 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 17, 15, 12, 10, 8, 6, 5, 4 or fewer amino acids or less or equally different peptide sequences. The antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments by less than or equal to about 4 amino acids or less. The antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments by less than or equal to about 3 amino acids or less. The antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments by less than or equal to about two amino acids or less. The antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments by less than or equal to about one amino acid or less. The amino acids may be contiguous, noncontiguous, or combinations thereof, e.g., an antibody region differs from a peptide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments by less than about 3 contiguous amino acids. peptide sequences. Alternatively, or in addition, the antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments by less than about two noncontiguous amino acids. In another example, an antibody region differs from a peptide sequence based on or derived from one or more immunoglobulin and/or immunoglobulin fragments by less than about 5 amino acids, wherein two of said amino acids are contiguous and two of said amino acids are non peptide sequences that are contiguous.

The antibody region may comprise a nucleotide sequence based on or derived from one or more antibody and/or immunoglobulin fragments and about 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 25, 20 , 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4 or fewer nucleotides or nucleotide sequences that differ by less than or equal to base pairs can The antibody region may comprise a nucleotide sequence that differs by less than or equal to about 15 nucleotides or base pairs from a nucleotide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The antibody region may comprise a nucleotide sequence that differs by less than or equal to about 12 nucleotides or base pairs from a nucleotide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The antibody region may comprise a nucleotide sequence that differs by less than or equal to about 9 nucleotides or base pairs from a nucleotide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The antibody region may comprise a nucleotide sequence that differs by less than or equal to about 6 nucleotides or base pairs from a nucleotide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The antibody region may comprise a nucleotide sequence that differs by less than or equal to about 4 nucleotides or base pairs from a nucleotide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The antibody region may comprise a nucleotide sequence that differs by less than or equal to about 3 nucleotides or base pairs from a nucleotide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The antibody region may comprise a nucleotide sequence that differs by less than or equal to about 2 nucleotides or base pairs from a nucleotide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments. The antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments by less than or equal to about 1 nucleotide or base pair. Nucleotides or base pairs may be contiguous, discontinuous, or combinations thereof. For example, an antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more immunoglobulins and/or immunoglobulin fragments by less than about 3 consecutive nucleotides or base pairs. Alternatively, or additionally, the antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more immunoglobulin and/or immunoglobulin fragments by less than about two noncontiguous nucleotides or base pairs. In another example, the antibody region differs from a nucleotide sequence based on or derived from one or more immunoglobulin and/or immunoglobulin fragments by less than about 5 nucleotides or base pairs, two of said nucleotides or base pairs being contiguous and said Two of the nucleotides or base pairs may comprise a nucleotide sequence that is non-contiguous.

The peptide sequence of the antibody region may differ from the peptide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by one or more amino acid substitutions. The peptide sequence of an antibody region may differ from the peptide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by two or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by three or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by four or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by 5 or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by at least 6 amino acid substitutions. The peptide sequence of the antibody region may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 17 with the peptide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived. , 20, 25 or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived about 20-30, 30-40, 40-50, 50-60, 60-70, 80-90, 90- 100, 100-150, 150-200, 200-300 or more amino acid substitutions.

The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by one or more nucleotide and/or base pair substitutions. The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by two or more nucleotide and/or base pair substitutions. The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by three or more nucleotide and/or base pair substitutions. The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by four or more nucleotide and/or base pair substitutions. The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by at least 5 nucleotides and/or base pair substitutions. The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by at least 6 nucleotides and/or base pair substitutions. The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by at least 9 nucleotides and/or base pair substitutions. The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by at least 12 nucleotides and/or base pair substitutions. The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by at least 15 nucleotides and/or base pair substitutions. The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by at least 18 nucleotides and/or base pair substitutions. The nucleotide sequence of an antibody region may differ from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived by 20, 22, 24, 25, 27, 30 or more nucleotides and/or base pair substitutions. The nucleotide sequence of the antibody region differs from the nucleotide sequence of the immunoglobulin or immunoglobulin fragment on which it is based and/or derived about 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90- 100, 100-200, 200-300, 300-400 or more nucleotides and/or base pair substitutions.

The antibody region may comprise at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids. The antibody region is at least about 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675 , 700 or more amino acids. The antibody region may comprise at least about 100 amino acids. The antibody region may comprise at least about 200 amino acids. The antibody region may comprise at least about 400 amino acids. The antibody region may comprise at least about 500 amino acids. The antibody region may comprise at least about 600 amino acids.

The antibody region may comprise less than about 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200 or 1100 amino acids. The antibody region may comprise less than about 1000, 950, 900, 850, 800, 750, or 700 amino acids. The antibody region may comprise less than about 1500 amino acids. The antibody region may comprise less than about 1000 amino acids. The antibody region may comprise less than about 800 amino acids. The antibody region may comprise less than about 700 amino acids.

The immunoglobulin fusion protein may further comprise an antibody region comprising no more than 30 contiguous amino acids of complementarity determining region 3 (CDR3). The antibody region is 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8 of CDR3. , 7, 6, 5, 4, 3, 2, 1 or fewer consecutive amino acids. The antibody region may comprise up to 15 contiguous amino acids of CDR3. The antibody region may comprise up to 14 contiguous amino acids of CDR3. The antibody region may comprise up to 13 contiguous amino acids of CDR3. The antibody region may comprise up to 12 contiguous amino acids of CDR3. The antibody region may comprise up to 11 contiguous amino acids of CDR3. The antibody region may comprise up to 10 contiguous amino acids of CDR3. The antibody region may comprise up to 9 contiguous amino acids of CDR3. The antibody region may comprise up to 8 contiguous amino acids of CDR3. The antibody region may comprise up to 7 contiguous amino acids of CDR3. The antibody region may comprise up to 6 contiguous amino acids of CDR3. The antibody region may comprise up to 5 contiguous amino acids of CDR3. The antibody region may comprise up to 4 contiguous amino acids of CDR3. The antibody region may comprise no more than 3 contiguous amino acids of CDR3. The antibody region may comprise no more than two contiguous amino acids of CDR3. The antibody region may comprise no more than one contiguous amino acid of CDR3. In some instances, the antibody region does not comprise CDR3.

The immunoglobulin fusion protein may comprise a first antibody region comprising no more than 6 contiguous amino acids of complementarity determining region 3 (CDR3). The first antibody region may comprise no more than 5 contiguous amino acids of CDR3. The first antibody region may comprise no more than 4 contiguous amino acids of CDR3. The first antibody region may comprise no more than 3 contiguous amino acids of CDR3. The first antibody region may comprise no more than two contiguous amino acids of CDR3. The first antibody region may comprise no more than one contiguous amino acid of CDR3. In some instances, the first antibody region does not comprise a CDR3.

The immunoglobulin fusion protein may further comprise a second antibody region comprising no more than 30 contiguous amino acids of complementarity determining region 3 (CDR3). The second antibody region is 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 of CDR3. , 8, 7, 6, 5, 4, 3, 2, 1 or less consecutive amino acids. The second antibody region may comprise up to 15 contiguous amino acids of CDR3. The second antibody region may comprise up to 14 contiguous amino acids of CDR3. The second antibody region may comprise up to 13 contiguous amino acids of CDR3. The second antibody region may comprise no more than 12 contiguous amino acids of CDR3. The second antibody region may comprise up to 11 contiguous amino acids of CDR3. The second antibody region may comprise up to 10 contiguous amino acids of CDR3. The second antibody region may comprise up to 9 contiguous amino acids of CDR3. The second antibody region may comprise no more than 8 contiguous amino acids of CDR3. The second antibody region may comprise no more than 7 contiguous amino acids of CDR3. The second antibody region may comprise up to 6 contiguous amino acids of CDR3. The second antibody region may comprise no more than 5 contiguous amino acids of CDR3. The second antibody region may comprise no more than 4 contiguous amino acids of CDR3. The second antibody region may comprise no more than 3 contiguous amino acids of CDR3. The second antibody region may comprise no more than two contiguous amino acids of CDR3. The second antibody region may comprise no more than one contiguous amino acid of CDR3. In some instances, the second antibody region does not comprise a CDR3.

The antibody region may comprise an amino acid sequence based on or derived from any one of SEQ ID NOs: 19-36 and 271-273. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 19-36 and 271-273. The antibody region has an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 19-36 and 271-273. may include The antibody region may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 19-36 and 271-273. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 19-36 and 271-273. The antibody region may comprise an amino acid sequence that is at least about 50% identical to any one of SEQ ID NOs: 19-36 and 271-273. The antibody region has an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOs: 19-36 and 271-273. may include The antibody region may comprise an amino acid sequence that is at least about 70% identical to any one of SEQ ID NOs: 19-36 and 271-273. The antibody region may comprise an amino acid sequence that is at least about 80% identical to any one of SEQ ID NOs: 19-36 and 271-273. The antibody region may comprise an amino acid sequence that is 100% identical to any one of SEQ ID NOs: 19-36 and 271-273. In some embodiments, the antibody region comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, amino acid sequences that are 90%, 95%, or 97% homologous. In some embodiments, the antibody region comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical amino acid sequences.

the antibody region comprises an amino acid sequence comprising at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids based on or derived from any one of SEQ ID NOs: 19-36 and 271-273 can do. The antibody region is based on or derived from any one of SEQ ID NOs: 19-36 and 271-273 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 , an amino acid sequence comprising 450, 500 or more amino acids. The antibody region may comprise an amino acid sequence comprising 10 or more amino acids based on or derived from any one of SEQ ID NOs: 19-36 and 271-273. The antibody region may comprise an amino acid sequence comprising 50 or more amino acids based on or derived from any one of SEQ ID NOs: 19-36 and 271-273. The antibody region may comprise an amino acid sequence comprising 100 or more amino acids based on or derived from any one of SEQ ID NOs: 19-36 and 271-273. The antibody region may comprise an amino acid sequence comprising 200 or more amino acids based on or derived from any one of SEQ ID NOs: 19-36 and 271-273. The amino acids may be contiguous. Alternatively, or additionally, the amino acids are discontinuous. In some embodiments, the antibody region may comprise amino acids derived from any one of SEQ ID NOs: 19-36 and 271-273 and amino acids not derived from any one of SEQ ID NOs: 19-36 and 271-273. In some embodiments, the antibody region may comprise amino acids derived from one or more of SEQ ID NOs: 19-36 and 271-273 and amino acids not derived from any of SEQ ID NOs: 19-36 and 271-273 . In some embodiments, the antibody region comprises amino acids derived from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of SEQ ID NOs: 19-36 and 271-273.

The antibody region may be encoded by a nucleotide sequence based on or derived from any one of SEQ ID NOs: 1-18 and 268-270. The antibody region may be encoded by a nucleotide sequence that is at least about 50% homologous to any one of SEQ ID NOs: 1-18 and 268-270. The antibody region has a nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 1-18 and 268-270. can be coded by The antibody region may be encoded by a nucleotide sequence that is at least about 70% homologous to any one of SEQ ID NOs: 1-18 and 268-270. The antibody region may be encoded by a nucleotide sequence that is at least about 80% homologous to any one of SEQ ID NOs: 1-18 and 268-270. The antibody region may be encoded by a nucleotide sequence that is at least about 50% identical to any one of SEQ ID NOs: 1-18 and 268-270. The antibody region has a nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOs: 1-18 and 268-270. can be coded by The antibody region may be encoded by a nucleotide sequence that is at least about 70% identical to any one of SEQ ID NOs: 1-18 and 268-270. The antibody region may be encoded by a nucleotide sequence that is at least about 80% identical to any one of SEQ ID NOs: 1-18 and 268-270. The antibody region may be encoded by a nucleotide sequence that is 100% identical to any one of SEQ ID NOs: 1-18 and 268-270.

The antibody region is defined by a nucleotide sequence comprising at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-18 and 268-270. can be coded. The antibody region is 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 based on or derived from any one of SEQ ID NOs: 1-18 and 268-270. , 450, 500 or more nucleotides. The antibody region may be encoded by a nucleotide sequence comprising 600, 650, 700, 750, 800, 850, 900, 950, 1000 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-18 and 268-270. can The antibody region may be encoded by a nucleotide sequence comprising 1100, 1200, 1300, 1400, 1500 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-18 and 268-270. The antibody region may be encoded by a nucleotide sequence comprising 100 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-18 and 268-270. The antibody region may be encoded by a nucleotide sequence comprising at least 500 nucleotides based on or derived from any one of SEQ ID NOs: 1-18 and 268-270. The antibody region may be encoded by a nucleotide sequence comprising at least 1000 nucleotides based on or derived from any one of SEQ ID NOs: 1-18 and 268-270. The antibody region may be encoded by a nucleotide sequence comprising at least 1300 nucleotides based on or derived from any one of SEQ ID NOs: 1-18 and 268-270. The nucleotides may be contiguous. In some embodiments, the antibody region comprises a nucleotide sequence comprising nucleotides derived from any one of SEQ ID NOs: 1-18 and 268-270 and nucleotides not derived from any of SEQ ID NOs: 1-18 and 268-270. coded by In some embodiments, the antibody region is a nucleotide sequence comprising nucleotides derived from one or more of SEQ ID NOs: 1-18 and 268-270 and nucleotides not derived from any of SEQ ID NOs: 1-18 and 268-270 is coded by In some embodiments, the antibody region is encoded by a nucleotide sequence derived from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of SEQ ID NOs: 1-18 and 268-270.

non-antibody region

The immunoglobulin fusion proteins disclosed herein may comprise one or more non-antibody regions. The immunoglobulin fusion proteins disclosed herein may comprise two or more non-antibody regions. The immunoglobulin fusion proteins disclosed herein may comprise 3, 4, 5, 6, 7, 8, 9, 10 or more non-antibody regions.

The two or more non-antibody regions may be attached to more than one antibody region. The two or more non-antibody regions may be attached to the two or more antibody regions. The two or more non-antibody regions may be attached to more than one immunoglobulin chain. The two or more non-antibody regions may be attached to two or more immunoglobulin chains. The two or more non-antibody regions may be attached to one or more subunits within the one or more antibody regions. The two or more non-antibody regions may be attached to two or more subunits within the one or more antibody regions.

The non-antibody region may comprise one or more therapeutic agents. The non-antibody region may comprise two or more therapeutic agents. The non-antibody region may comprise 3, 4, 5, 6, 7 or more therapeutic agents. The therapeutic agent may be different. The therapeutic agents may be the same.

The non-antibody region may comprise one or more extender peptides. The non-antibody region may comprise two or more extender peptides. The non-antibody region may comprise 3, 4, 5, 6, 7 or more extender peptides. The extender peptide may be different. The extender peptides may be identical. In some embodiments, the extender peptide comprises an amino acid sequence having a secondary structure of an alpha helix. In some embodiments, the extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the extender fusion region comprises two extender peptides, wherein the two extender peptides are arranged to form a coiled coil. In some instances, the non-antibody region does not include an extender peptide. The extender peptide may directly link the therapeutic peptide to the antibody region.

The non-antibody region may comprise one or more linkers. The non-antibody region may comprise two or more linkers. The non-antibody region may comprise 3, 4, 5, 6, 7 or more linkers. The linkers may be different. The linkers may be identical. The linker may directly link the therapeutic agent to the antibody region. The linker may link the therapeutic peptide to the extender peptide. In some instances, the non-antibody region does not include a linker. In some embodiments, the linker peptide does not comprise an amino acid having an alpha helix or beta strand secondary structure.

The non-antibody region may comprise one or more protease cleavage sites. The non-antibody region may comprise two or more protease cleavage sites. The cleavage site may be different. The cleavage site may be the same. The cleavage site may directly link the therapeutic agent to the antibody region. The cleavage site may link the therapeutic agent to the linker peptide. The cleavage site may link the therapeutic agent to the extender peptide. In some embodiments, the therapeutic agent comprises a protease cleavage site. In some instances, the non-antibody region does not include a protease cleavage site.

The extender fusion region may comprise one or more connecting peptides. The linking peptide may comprise an extender peptide. The linking peptide may comprise a linker peptide. The linking peptide may comprise a protease cleavage site. A linking peptide may comprise any amino acid sequence arranged to link a therapeutic agent to an antibody region.

The non-antibody region may be inserted into the antibody region. Insertion of a non-antibody region into an antibody region may include removal or deletion of a portion of the antibody from which the antibody region is based. At least a portion of the heavy chain may be substituted with a non-antibody region. At least a portion of the light chain may be substituted with a non-antibody region. At least a portion of the V region may be substituted with a non-antibody region. At least a portion of the D region may be substituted with a non-antibody region. At least a portion of the J region may be substituted with a non-antibody region. At least a portion of the variable region may be substituted with a non-antibody region. At least a portion of the constant region may be substituted with a non-antibody region. At least a portion of the complementarity determining region (CDR) may be substituted with a non-antibody region. At least a portion of CDR1 may be substituted with a non-antibody region. At least a portion of CDR2 may be substituted with a non-antibody region. At least a portion of CDR3 may be substituted with a non-antibody region. non-antibody region at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% of the antibody or portion thereof; 70%, 75%, 80%, 85%, 90%, 95% or more may be substituted. For example, at least about 50% of a CDR may be substituted with a non-antibody region. Non-antibody regions may replace at least about 70% of the CDRs. About 80% of the CDRs can be substituted with non-antibody regions. Non-antibody regions may replace at least about 90% of the CDRs. About 95% of the CDRs can be substituted with non-antibody regions.

The non-antibody region comprises (a) one or more extender peptides; (b) one or more therapeutic agents; (c) optionally one or more linkers; and (d) optionally, one or more proteolytic cleavage sites. In some embodiments, the one or more extender peptides comprise an amino acid sequence having an alpha helix secondary structure. In some cases, an immunoglobulin fusion protein comprising an antibody region and a non-antibody region, wherein the non-antibody region comprises one or more extender peptides comprising amino acids having an alpha helix secondary structure, It is referred to as a coil immunoglobulin fusion protein.

The non-antibody region comprises (a) one or more linker peptides; (b) one or more therapeutic agents; and (c) optionally, one or more proteolytic cleavage sites. In some embodiments, the one or more linker peptides do not comprise an amino acid sequence having a secondary structure of an alpha helix or beta strand. In some cases, the immunoglobulin fusion protein comprising an antibody region and a non-antibody region, wherein at least one linker peptide does not comprise an amino acid sequence having an alpha helix or beta strand secondary structure, wherein the referred to as globulin fusion proteins.

In some embodiments, the non-antibody region is an extender fusion region.

extender fusion zone

The immunoglobulin fusion proteins disclosed herein may comprise one or more extender fusion regions. The immunoglobulin fusion protein may comprise two or more extender fusion regions. The immunoglobulin fusion protein may comprise 3, 4, 5, 6, 7, 8, 9, 10 or more extender fusion regions.

The two or more extender fusion regions may be attached to more than one antibody region. The two or more extender fusion regions may be attached to the two or more antibody regions. The two or more extender fusion regions may be attached to one or more immunoglobulin chains. The two or more extender fusion regions may be attached to two or more immunoglobulin chains. The two or more extender fusion regions may be attached to one or more subunits of the one or more antibody regions. The two or more extender fusion regions may be attached to two or more subunits of the one or more antibody regions.

The extender fusion region may comprise one or more extender peptides. The extender fusion region may comprise two or more extender peptides. The extender fusion region may comprise 3, 4, 5, 6 or more extender peptides. The extender peptide may be different. The extender peptides may be identical. In some embodiments, the extender peptide comprises an amino acid sequence having a secondary structure of an alpha helix. In some embodiments, the extender peptide does not comprise an amino acid having a beta strand secondary structure. In some embodiments, the extender fusion region comprises two extender peptides, wherein the two extender peptides are arranged to form a coiled coil. In some instances, the extender fusion region does not comprise an extender peptide. In some embodiments, the extender peptide directly links the therapeutic agent to the antibody region.

The extender fusion region may comprise one or more therapeutic agents. The extender fusion region may comprise two or more therapeutic agents. The extender fusion region may comprise 3, 4, 5, 6, 7 or more therapeutic agents. The therapeutic agent may be different. The therapeutic agents may be the same.

The extender fusion region may comprise one or more linkers. The extender fusion region may comprise two or more linkers. The extender fusion region may comprise 3, 4, 5, 6, 7 or more linkers. The linkers may be different. The linkers may be identical. The linker may link the therapeutic agent to the extender peptide. The linker may directly link the therapeutic agent to the antibody region. In some instances, the extender fusion region does not include a linker. In some embodiments, the linker peptide does not comprise an amino acid having an alpha helix or beta strand secondary structure.

The extender fusion region may comprise one or more protease cleavage sites. The extender fusion region may comprise two or more protease cleavage sites. The cleavage site may be different. The cleavage site may be the same. The cleavage site may directly link the therapeutic agent to the antibody region. The cleavage site may link the therapeutic agent to the extender peptide. The cleavage site may link the therapeutic agent to the linker peptide. In some instances, the extender fusion region does not include a protease cleavage site.

The extender fusion region may comprise one or more connecting peptides. The linking peptide may comprise an extender peptide. The linking peptide may comprise a linker peptide. The linking peptide may comprise a protease cleavage site. A linking peptide may comprise any sequence of amino acids configured to link a therapeutic agent to an antibody region.

The immunoglobulin fusion proteins disclosed herein may comprise an antibody region attached to an extender fusion region. The extender fusion region may be attached to the N-terminus, C-terminus, or N- and C-terminus of the antibody region. The antibody region may be directly attached to the extender fusion region. Alternatively, or in addition, the antibody region may be attached indirectly to a non-antibody sequence. Attachment of the extender fusion region to the antibody region may comprise a covalent attachment. Attachment may comprise fusion of an extender fusion region to an antibody region. Attachment may include chemical conjugation.

Alternatively, or in addition, attachment comprises insertion of an extender fusion region into the antibody region. The extender fusion region may be inserted into the heavy chain of the antibody region. The extender fusion region may be inserted into the light chain of the antibody region. The extender fusion region can be inserted into the variable domain of the antibody region. The extender fusion region may be inserted into the constant domain of the antibody region. The extender fusion region may be inserted into the complementarity determining region (CDR) of the antibody region.

The extender fusion region may replace at least a portion of the antibody on which the antibody region is based or derived. The extender fusion region may replace at least a portion of the heavy chain of the antibody upon which the antibody region may be based or derived. The extender fusion region may replace at least a portion of the light chain of the antibody from which the antibody region may be based or derived. The extender fusion region may replace at least a portion of the variable domain of an antibody from which the antibody region may be based or derived. The extender fusion region may replace at least a portion of the constant domain of an antibody from which the antibody region may be based or derived. The extender fusion region may replace at least a portion of a complementarity determining region (CDR) of an antibody from which the antibody region may be based or derived. The extender fusion region may replace at least a portion of a CDR1, CDR2, CDR3, or combination thereof of an antibody on which the antibody or fragment thereof may be based or derived. The extender fusion region may replace at least a portion of a CDR3 of an antibody upon which the antibody region may be based or derived.

The extender fusion region may substitute at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or more amino acids of the antibody from which the antibody region is based and derived. The extender fusion region may substitute at least about one or more amino acids of the antibody from which the antibody region is based or derived. The extender fusion region may be substituted for at least about 3 or more amino acids of the antibody from which the antibody region is based or derived. The extender fusion region may be substituted for at least about 5 or more amino acids of the antibody from which the antibody region is based or derived.

the extender fusion region comprises at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more amino acids can do. The extender fusion region may comprise at least about 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000 or more amino acids. The extender fusion region may comprise at least about 10 or more amino acids. The extender fusion region may comprise at least about 25 or more amino acids. The extender fusion region may comprise at least about 50 or more amino acids. The extender fusion region may comprise at least about 75 or more amino acids. The extender fusion region may comprise at least about 100 or more amino acids.

The extender fusion region may comprise less than about 2000, 1500, 1000, 900, 800, 700, 600, or 500 amino acids. The extender fusion region may comprise less than about 450, 400, 350, 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 70, 60, 50 amino acids. The extender fusion region may comprise less than about 400 amino acids. The extender fusion region may comprise less than about 300 amino acids. The extender fusion region may comprise less than about 250 amino acids.

The extender fusion region may comprise between about 10 and about 1000 amino acids. The extender fusion region may comprise between about 10 and about 500 amino acids. The extender fusion region may comprise between about 10 and about 400 amino acids. The extender fusion region may comprise between about 10 and about 300 amino acids. The extender fusion region may comprise between about 10 and about 250 amino acids. The extender fusion region may comprise between about 20 and about 500 amino acids. The extender fusion region may comprise between about 20 and about 400 amino acids. The extender fusion region may comprise between about 20 and about 300 amino acids.

The extender fusion region comprises (a) one or more extender peptides; (b) one or more therapeutic agents; (c) optionally one or more linkers; and (d) optionally, one or more proteolytic cleavage sites. Representative extender fusion regions are shown in Figures 2A-G. For example, as shown in FIG. 2A , the extender fusion region comprises an extender peptide 210 and a therapeutic agent 220 . As shown in FIG. 2B , the extender fusion region comprises two extender peptides 210 , 230 and a therapeutic agent 220 . As shown in FIG. 2C , the extender fusion region comprises an extender peptide 210 and a therapeutic agent 220 connected by a linker 240 . As shown in FIG. 2D , the extender fusion region comprises an extender peptide 210 and a therapeutic agent 220 flanked by two linkers 240 and 250 . 2E, the extender fusion region comprises an extender peptide 210, a therapeutic agent 220, and a proteolytic cleavage site 260, wherein the proteolytic cleavage site 260 is disposed between the extender peptide and the therapeutic agent. is inserted. As shown in FIG. 2F , the extender fusion region comprises two extender peptides 210 , 230 , two linkers 240 , 250 and a therapeutic agent 220 . As shown in FIG. 2G , the extender fusion region comprises two extender peptides 210 , 230 , two linkers 240 , 250 , a proteolytic cleavage site 260 and a therapeutic agent 220 .

The extender fusion region comprises (a) a first extender peptide, wherein the first extender comprises (i) an amino acid sequence comprising a secondary structure of an alpha helix and (ii) no more than 7 amino acids based on or derived from a very long CDR3. peptides; and (b) a therapeutic agent. The extender fusion region may further comprise one or more additional extender peptides comprising at least one secondary structure. The extender fusion region may further comprise one or more linkers. The extender fusion region may further comprise one or more proteolytic cleavage sites.

The extender fusion region comprises (a) a first extender peptide comprising a first extender peptide comprising (i) an amino acid sequence comprising a secondary structure of an alpha helix and (ii) an amino acid sequence not comprising a very long CDR3; and (b) a first therapeutic agent. The extender fusion region may further comprise one or more additional extender peptides comprising at least one secondary structure. The extender fusion region may further comprise one or more linkers. The extender fusion region may further comprise one or more proteolytic cleavage sites.

The extender fusion region comprises (a) one or more extender peptides; (b) one or more therapeutic agents; (c) optionally one or more linkers; and (d) optionally, one or more proteolytic cleavage sites. In some embodiments, the one or more extender peptides comprise an amino acid sequence having an alpha helix secondary structure. In some cases, an immunoglobulin fusion protein comprising an antibody region and an extender fusion region, wherein the extender fusion region comprises one or more extender peptides comprising amino acids having an alpha helix secondary structure, It is referred to as a coil immunoglobulin fusion protein.

The extender fusion region comprises (a) one or more linker peptides; (b) one or more therapeutic agents; and (c) optionally, one or more proteolytic cleavage sites. In some embodiments, the one or more linker peptides do not comprise an amino acid sequence having a secondary structure of an alpha helix or beta strand. In some cases, the immunoglobulin fusion protein comprises an antibody region and an extender fusion region, wherein the one or more linker peptides do not comprise an amino acid sequence having an alpha-helix or beta-strand secondary structure. referred to as immunoglobulin fusion proteins.

In some embodiments, the extender fusion region does not comprise an amino acid that is based on or derived from an antibody. In some instances, the extender fusion region is a non-antibody region.

extender peptide

The immunoglobulin fusion proteins disclosed herein may comprise one or more extender peptides. The immunoglobulin fusion proteins disclosed herein may comprise two or more extender peptides. The one or more extender peptides may be attached to the N-terminus, C-terminus, or N- and C-terminus of the therapeutic agent. One or more extender peptides may be attached to each end of the therapeutic agent. The one or more extender peptides may be attached to different ends of the therapeutic agent.

The extender fusion region of an immunoglobulin fusion protein disclosed herein may comprise one or more extender peptides. The extender fusion region may comprise two or more extender peptides. The extender fusion region may comprise three or more extender peptides. The extender fusion region may comprise four or more extender peptides. The extender fusion region may comprise five or more extender peptides. The extender fusion region may comprise a first extender peptide and a second extender peptide.

The extender peptide may comprise one or more secondary structures. The extender peptide may comprise two or more secondary structures. The extender peptide may comprise 3, 4, 5, 6, 7 or more secondary structures. The two or more extender peptides may include one or more secondary structures. The two or more extender peptides may comprise two or more secondary structures. The two or more extender peptides may comprise 3, 4, 5, 6, 7 or more secondary structures. Each extender peptide may comprise at least one secondary structure. The secondary structures of the two or more extender peptides may be the same. Alternatively, the secondary structures of the two or more extender peptides may be different.

Alternatively, or additionally, one or more secondary structures may include one or more alpha helices. The extender peptide may comprise two or more alpha helices. For example, the first extender peptide comprises a first alpha helix and the second extender peptide comprises a second alpha helix. The extender peptide may comprise 3, 4, 5, 6, 7 or more alpha helices. The two or more alpha helices may be antiparallel. The two or more alpha helices may be parallel. Two or more alpha helices may form one or more coiled coil domains.

The one or more extender peptides may comprise at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids. The one or more extender peptides are at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 It may contain more than one amino acid. The one or more extender peptides may comprise at least about 35, 40, 45, 50, 60, 70, 80, 90, 100 or more amino acids.

The one or more extender peptides may comprise less than about 100 amino acids. The one or more extender peptides may comprise less than about 95, 90, 85, 80, 75, 70, 65, 60, 55, or 50 amino acids. The one or more extender peptides may comprise less than about 90 amino acids. The one or more extender peptides may comprise less than about 80 amino acids. The one or more extender peptides may comprise less than about 70 amino acids.

The two or more extender peptides may be the same length. For example, the first extender peptide and the second extender peptide are the same length. Alternatively, the two or more extender peptides are of different lengths. In another example, the first extender peptide and the second extender peptide are different in length. The two or more extender peptides are at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids. may be different in length. The two or more extender peptides may differ in length by at least about one amino acid. The two or more extender peptides may differ in length by at least about 3 or more amino acids. The two or more extender peptides may differ in length by at least about 5 or more amino acids.

The extender peptide may be adjacent to the antibody region. The extender peptide may be attached to the N-terminus, C-terminus, or N- and C-terminus of the antibody region. The extender peptide may be adjacent to the non-antibody region. The extender peptide may be attached to the N-terminus, C-terminus, or N- and C-terminus of the non-antibody region. The extender peptide may be adjacent to the therapeutic agent. The extender peptide may be attached to the N-terminus, C-terminus, or N- and C-terminus of the therapeutic agent. The extender peptide may be adjacent to the linker. The extender peptide may be attached to the N-terminus, C-terminus, or N- and C-terminus of the linker. The extender peptide may be adjacent to a proteolytic cleavage site. The extender peptide may be attached to the N-terminus, C-terminus, or N- and C-terminus of the proteolytic cleavage site.

The extender peptide may link a therapeutic agent to the antibody region. An extender peptide may be placed between the antibody region and the therapeutic, linker, and/or proteolytic cleavage site. The extender peptide may be placed between two or more antibody regions, therapeutic agents, linkers, proteolytic cleavage sites, or combinations thereof. The extender peptide may be at the N-terminus of the antibody region, therapeutic agent, linker, proteolytic cleavage site, or a combination thereof. The extender peptide may be at the C-terminus of the antibody region, therapeutic agent, linker, proteolytic cleavage site, or a combination thereof.

The extender peptide may comprise an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. The extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. The extender peptide is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or more homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. adult amino acid sequences. The extender peptide may comprise an amino acid sequence that is at least about 70% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. The extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. The extender peptide may comprise an amino acid sequence that is at least about 85% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175.

The first extender peptide may comprise an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. The first extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. The first extender peptide comprises at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% of an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. It may include amino acid sequences that are aberrantly homologous. The first extender peptide may comprise an amino acid sequence that is at least about 75% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. The first extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175.

The first extender peptide may comprise an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-153. The first extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-153. The first extender peptide comprises at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% of an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-153. It may include amino acid sequences that are aberrantly homologous. The first extender peptide may comprise an amino acid sequence that is at least about 75% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-153. The first extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-153.

The second extender peptide may comprise an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. The second extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. The second extender peptide is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. It may include amino acid sequences that are aberrantly homologous. The second extender peptide may comprise an amino acid sequence that is at least about 70% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175. The second extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 144-175.

The second extender peptide may comprise an amino acid sequence based on or derived from any one of SEQ ID NOs: 154-163. The second extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 154-163. The second extender peptide is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% to an amino acid sequence based on or derived from any one of SEQ ID NOs: 154-163. It may include amino acid sequences that are aberrantly homologous. The second extender peptide may comprise an amino acid sequence that is at least about 70% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 154-163. The second extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 154-163.

The extender peptides disclosed herein may be based on or derived from CDR3. CDR3 may be a very long CDR3. An “extremely long CDR3” or “extremely long CDR3 sequence,” as used interchangeably herein, may include a CDR3 that is not derived from a human antibody sequence. A very long CDR3 can be 35 amino acids long, eg, 40 amino acids long, 45 amino acids long, 50 amino acids long, 55 amino acids long, or 60 amino acids long. The very long CDR3 may be a heavy chain CDR3 (CDR-H3 or CDRH3). A very long CDR3 may include a sequence derived from or based on a sequence of a ruminant (eg, bovine). A very long CDR3 may contain more than one cysteine motif. A very long CDR3 may comprise at least 3 or more cysteine residues, eg, 4 or more cysteine residues, 6 or more cysteine residues, or 8 or more cysteine residues. Additional details on the very long CD3 can be found in Saini SS, et al. (Exceptionally long CDR3H region with multiple cystein residues in functional bovine IgM antibodies, European Journal of Immunology , 1999), Zhang Y, et al. (Functional antibody CDR3 fusion proteins with enhanced pharmacological properties, Angew Chem Int Ed Engl , 2013), Wang F, et al. (Reshaping antibody diversity, Cell , 2013) and US Pat. No. 6,740,747.

The extender peptide may comprise up to 7 amino acids based on or derived from a CDR. The extender peptide may comprise up to 6, 5, 4, 3, 2, 1 or fewer amino acids based on or derived from a CDR. The amino acids may be contiguous. The amino acids may be discontinuous. The CDR may be CDR1. The CDR may be CDR2. The CDR may be CDR3. The CDR may be a very long CDR.

The extender peptide may be based on or derived from a CDR other than CDR3. The extender peptide may comprise 10 or fewer amino acids based on or derived from CDR3. The extender peptide may comprise no more than 9, 8, 7, 6, 5, 4, 3, 2, 1 or fewer amino acids based on or derived from CDR3. The extender peptide may comprise up to 8 amino acids based on or derived from CDR3. The extender peptide may comprise up to 7 amino acids based on or derived from CDR3. The extender peptide may comprise 5 or fewer amino acids based on or derived from CDR3.

The extender peptide may comprise an amino acid sequence that is less than about 50% identical to an amino acid sequence comprising a very long CDR3. The extender peptide may comprise an amino acid sequence that is less than about 45%, 40%, 35%, 30%, 25%, 20%, 25%, or 10% identical to the amino acid sequence comprising the very long CDR3. The extender peptide may comprise an amino acid sequence that is less than about 30% identical to an amino acid sequence comprising a very long CDR3. The extender peptide may comprise an amino acid sequence that is less than about 25% identical to an amino acid sequence comprising a very long CDR3. The extender peptide may comprise an amino acid sequence that is less than about 20% identical to an amino acid sequence comprising a very long CDR3.

Extender peptides contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more amino acids attached to or inserted into a region based on the very long CDR3 of the extender peptide. may include The extender peptide may comprise one or more amino acids attached to or inserted into a portion based on the very long CDR3 of the extender peptide. The extender peptide may comprise three or more amino acids attached to or inserted into a portion based on the very long CDR3 of the extender peptide. The extender peptide may comprise 5 or more amino acids attached to or inserted into a portion based on the very long CDR3 of the extender peptide. Two or more amino acids attached to or inserted into a very long CDR3 may be contiguous. Alternatively, or additionally, two or more amino acids attached to or inserted into a moiety based on a very long CDR3 are not contiguous.

The extender peptide may contain no more than 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 amino acids attached to or inserted into a portion based on the very long CDR3 of the extender peptide. have. The extender peptide may comprise up to 20 amino acids attached to or inserted into a portion based on the very long CDR3 of the extender peptide. The extender peptide may comprise up to 15 amino acids attached to or inserted into a portion based on the very long CDR3 of the extender peptide. The extender peptide may comprise up to 10 amino acids attached to or inserted into a portion based on the very long CDR3 of the extender peptide. Amino acids attached to or inserted into very long CDR3 may be contiguous. Alternatively, or additionally, the amino acids attached to or inserted into the very long CDR3 are not contiguous.

The extender peptide may comprise the sequence X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ X ⁸ X ⁹ X ¹⁰ X ¹¹ X ¹² X ¹³ X ¹⁴ (SEQ ID NO: 144). In some embodiments, the first extender peptide comprises the sequence X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ X ⁸ X ⁹ X ¹⁰ X ¹¹ X ¹² X ¹³ X ¹⁴ (SEQ ID NO: 144). The first extender peptide, in some instances, is located between the amino terminus of the therapeutic agent and the antibody region. X ¹ -X ¹⁴ may be independently selected from positively charged amino acids or hydrophobic amino acids. X ¹ -X ¹⁴ are independent from the group comprising alanine (A), asparagine (N), isoleucine (I) leucine (L), valine (V), glutamine (Q), glutamic acid (E) and lysine (K) can be selected as X ¹ -X ¹⁴ may be independently selected from the group comprising alanine (A), leucine (L) and lysine (K). Alanine may comprise at least about 30% of the total amino acid composition. Alanine may comprise less than about 70% of the total amino acid composition. Leucine may comprise at least about 20% of the total amino acid composition. Leucine may comprise less than about 50% of the total amino acid composition. Lysine may comprise at least about 20% of the total amino acid composition. Lysine may comprise less than about 50% of the total amino acid composition. The hydrophobic amino acid may comprise at least about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 60% of the total amino acid composition. The hydrophobic amino acid may comprise at least about 70% of the total amino acid composition. Hydrophobic amino acids may comprise less than about 90% of the total amino acid composition.

The extender peptide may comprise the sequence (X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ ) _n (SEQ ID NO: 145). In some embodiments, the first extender peptide comprises the sequence (X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ ) _n (SEQ ID NO: 145). A first extender peptide, in some instances, is located between the amino terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3. X ¹ -X ⁷ may be independently selected from positively charged amino acids or hydrophobic amino acids. X ¹ -X ⁷ are from the group comprising alanine (A), asparagine (N), isoleucine (I), leucine (L), valine (V), glutamine (Q), glutamic acid (E) and lysine (K). can be independently selected. Alanine (A) may comprise at least about 30% of the total amino acid composition. Alanine (A) may comprise at least less than about 70% of the total amino acid composition. Leucine may comprise at least about 20% of the total amino acid composition. Leucine may comprise at least less than about 50% of the total amino acid composition. Lysine may comprise at least about 20% of the total amino acid composition. Lysine may comprise less than about 50% of the total amino acid composition. Asparagine may account for about 50% of the total amino acid composition. Isoleucine may account for about 50% of the total amino acid composition. Valine may account for about 50% of the total amino acid composition. Glutamine may account for about 50% of the total amino acid composition. Glutamic acid may account for about 50% of the total amino acid composition. The hydrophobic amino acid may comprise at least about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 60% of the total amino acid composition. The hydrophobic amino acid may comprise at least about 70% of the total amino acid composition. Hydrophobic amino acids may comprise less than about 90% of the total amino acid composition.

The extender peptide may comprise the sequence X ^a X ^b X ^c X ^d (X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ ) _n (SEQ ID NO: 146). In some embodiments, the first extender peptide comprises the sequence X ^a X ^b X ^c X ^d (X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ ) _n (SEQ ID NO: 146). The first extender peptide, in some instances, is located between the amino terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3. X ^a , X ^b and X ^d may be independently selected from hydrophobic amino acids. X ^c may be a polar, uncharged amino acid. X ^a , X ^b and X ^d may be the same amino acid. X ^a , X ^b and X ^d may be different amino acids. X ¹ -X ⁷ may be independently selected from positively charged amino acids or hydrophobic amino acids. X ¹ -X ⁷ are from the group comprising alanine (A), asparagine (N), isoleucine (I), leucine (L), valine (V), glutamine (Q), glutamic acid (E) and lysine (K). can be independently selected. X ¹ -X ⁷ may be independently selected from the group comprising A, L and K. A may comprise at least about 30% of the total amino acid composition. A may comprise less than about 70% of the total amino acid composition. L may comprise at least about 20% of the total amino acid composition. L may comprise less than about 50% of the total amino acid composition. K may comprise at least about 20% of the total amino acid composition. K may comprise less than about 50% of the total amino acid composition. The hydrophobic amino acid may comprise at least about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 60% of the total amino acid composition. The hydrophobic amino acid may comprise at least about 70% of the total amino acid composition. Hydrophobic amino acids may comprise less than about 90% of the total amino acid composition. In some embodiments, X ^a is glycine (G). In some embodiments, X ^b is G. In some embodiments, X ^d is glycine. X ^a , X ^b and X ^d may be glycine (G). X ^c may be serine (S).

The extender peptide may comprise the sequence X ^a X ^b X ^c X ^d (AKLAALK) _n (SEQ ID NO: 147). In some embodiments, the first extender peptide comprises the sequence X ^a X ^b X ^c X ^d (AKLAALK) _n (SEQ ID NO: 147). The first extender peptide, in some instances, is located between the amino terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3. X ^a , X ^b and X ^d may be independently selected from hydrophobic amino acids. X ^c may be a polar, uncharged amino acid. X ^a , X ^b and X ^d may be the same amino acid. X ^a , X ^b and X ^d may be different amino acids. In some embodiments, X ^a is glycine (G). In some embodiments, X ^b is glycine. In some embodiments, X ^d is glycine. X ^a , X ^b and X ^d may be glycine (G). X ^c may be serine (S).

The extender peptide may comprise the sequence (AKLAALK) _n (SEQ ID NO: 148). In some embodiments, the first extender peptide comprises the sequence (AKLAALK) _n (SEQ ID NO: 148). The first extender peptide, in some instances, is located between the amino terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3.

The extender peptide may comprise the sequence GGSG(AKLAALK) _n (SEQ ID NO: 149). In some embodiments, the first extender peptide comprises the sequence GGSG(AKLAALK) _n (SEQ ID NO: 149). The first extender peptide, in some instances, is located between the amino terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3.

The extender peptide may comprise the sequence X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ X ⁸ X ⁹ X ¹⁰ X ¹¹ X ¹² X ¹³ X ¹⁴ (SEQ ID NO: 154), wherein X ¹ -X ¹⁴ is independently selected from negatively charged amino acids or hydrophobic amino acids. In some embodiments, the second extender peptide comprises the sequence X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ X ⁸ X ⁹ X ¹⁰ X ¹¹ X ¹² X ¹³ X ¹⁴ (SEQ ID NO: 154), wherein X ¹ -X ¹⁴ are independently selected from negatively charged amino acids or hydrophobic amino acids. The second extender peptide, in some instances, is located between the carboxyl terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3. In some embodiments, X ¹ -X ¹⁴ are independently selected from the group comprising alanine (A), leucine (L), and glutamic acid (E). In one embodiment, A comprises at least about 30% of the total amino acid composition. In one embodiment, A comprises less than about 70% of the total amino acid composition. In one embodiment, L comprises at least about 20% of the total amino acid composition. In one embodiment, L comprises less than about 50% of the total amino acid composition. In one embodiment, E comprises at least about 20% of the total amino acid composition. In one embodiment, E comprises less than about 50% of the total amino acid composition. In one embodiment, the hydrophobic amino acids comprise at least about 50% of the total amino acid composition. In one embodiment, the hydrophobic amino acids comprise at least about 60% of the total amino acid composition. In one embodiment, the hydrophobic amino acids comprise at least about 70% of the total amino acid composition. In one embodiment, the hydrophobic amino acids comprise less than about 90% of the total amino acid composition.

The second extender peptide may comprise the sequence (X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ ) _n (SEQ ID NO: 155). The second extender peptide comprises the sequence (X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ ) _n (SEQ ID NO: 155). The second extender peptide, in some instances, is located between the carboxyl terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3. X ¹ -X ⁷ may be independently selected from positively charged amino acids or hydrophobic amino acids. X ¹ -X ⁷ are from the group comprising alanine (A), asparagine (N), isoleucine (I), leucine (L), valine (V), glutamine (Q), glutamic acid (E) and lysine (K). can be independently selected. Alanine (A) may comprise at least about 30% of the total amino acid composition. Alanine (A) may comprise less than about 70% of the total amino acid composition. Leucine may comprise at least about 20% of the total amino acid composition. Leucine may comprise less than about 50% of the total amino acid composition. Lysine may comprise at least about 20% of the total amino acid composition. Lysine may comprise less than about 50% of the total amino acid composition. Asparagine may account for about 50% of the total amino acid composition. Isoleucine may account for about 50% of the total amino acid composition. Valine may account for about 50% of the total amino acid composition. Glutamine may account for about 50% of the total amino acid composition. Glutamic acid may account for about 50% of the total amino acid composition. The hydrophobic amino acid may comprise at least about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 60% of the total amino acid composition. The hydrophobic amino acid may comprise at least about 70% of the total amino acid composition. Hydrophobic amino acids may comprise less than about 90% of the total amino acid composition.

The extender peptide may comprise the sequence (X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ ) _n X ^a X ^b X ^c X ^d (SEQ ID NO: 156). In some embodiments, the second extender peptide comprises the sequence (X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ ) _n X ^a X ^b X ^c X ^d (SEQ ID NO: 156). The second extender peptide, in some instances, is located between the carboxyl terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3. X ¹ -X ⁷ may be independently selected from positively charged amino acids or hydrophobic amino acids. X ¹ -X ⁷ may be independently selected from the group comprising alanine (A), leucine (L) and lysine (K). A may comprise at least about 30% of the total amino acid composition. A may comprise less than about 70% of the total amino acid composition. L may comprise at least about 20% of the total amino acid composition. L may comprise less than about 50% of the total amino acid composition. K may comprise at least about 20% of the total amino acid composition. K may comprise less than about 50% of the total amino acid composition. The hydrophobic amino acid may comprise at least about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 60% of the total amino acid composition. The hydrophobic amino acid may comprise at least about 70% of the total amino acid composition. Hydrophobic amino acids may comprise less than about 90% of the total amino acid composition. X ^a , X ^b and X ^d may be independently selected from hydrophobic amino acids. X ^c may be a polar, uncharged amino acid. X ^a , X ^b and X ^d may be the same amino acid. X ^a , X ^b and X ^d may be different amino acids. In some embodiments, X ^a is glycine (G). In some embodiments, X ^b is glycine. In some embodiments, X ^d is glycine. X ^a , X ^b and X ^d may be glycine (G). X ^c may be serine (S).

The extender peptide may comprise the sequence (ELAALEA) _n X ^a X ^b X ^c X ^d (SEQ ID NO: 157). In some embodiments, the second extender peptide comprises the sequence (ELAALEA) _n X ^a X ^b X ^c X ^d (SEQ ID NO: 157). The second extender peptide, in some instances, is located between the carboxyl terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3. X ^a , X ^b and X ^d may be independently selected from hydrophobic amino acids. X ^c may be a polar, uncharged amino acid. X ^a , X ^b and X ^d may be the same amino acid. X ^a , X ^b and X ^d may be different amino acids. In some embodiments, X ^a is glycine (G). In some embodiments, X ^b is glycine. In some embodiments, X ^d is glycine. X ^a , X ^b and X ^d may be glycine (G). X ^c may be serine (S).

The extender peptide may comprise the sequence (ELAALEA) _n (SEQ ID NO: 158). In some embodiments, the second extender peptide comprises sequence (ELAALEA) _n (SEQ ID NO: 158). The second extender peptide, in some instances, is located between the carboxyl terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3.

The extender peptide may comprise the sequence (ELAALEA) _n GGSG (SEQ ID NO: 159). In some embodiments, the second extender peptide comprises the sequence (ELAALEA) _n GGSG (SEQ ID NO: 159). The second extender peptide, in some instances, is located between the carboxyl terminus of the therapeutic agent and the antibody region. In some embodiments, n is between about 1 and about 10. In some embodiments, n is between about 1 and about 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. N may be from about 1 to about 3.

The immunoglobulin fusion protein comprises (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 151; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 161. The immunoglobulin fusion protein comprises (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to the amino acid sequence of SEQ ID NO: 151; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to the amino acid sequence of SEQ ID NO: 161. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to the amino acid sequence of SEQ ID NO: 151. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to the amino acid sequence of SEQ ID NO: 161. The first extender peptide may comprise amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from the amino acid sequence of SEQ ID NO: 151. The first extender peptide may comprise amino acid sequencing comprising 5 or more amino acids based on or derived from the amino acid sequence of SEQ ID NO:151. The second extender peptide may comprise amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from the amino acid sequence of SEQ ID NO: 161. The second extender peptide may comprise amino acid sequencing comprising 5 or more amino acids based on or derived from the amino acid sequence of SEQ ID NO: 161.

The aliphatic amino acids may comprise at least about 20% of the total amino acids of the extender peptide. The aliphatic amino acids may comprise at least about 22%, 25%, 27%, 30%, 32%, 35%, 37%, 40%, 42%, 45% or more of the total amino acids of the extender peptide. The aliphatic amino acids may comprise at least about 22% of the total amino acids of the extender peptide. The aliphatic amino acids may comprise at least about 27% of the total amino acids of the extender peptide.

The aliphatic amino acids may comprise less than about 50% of the total amino acids of the extender peptide. The aliphatic amino acids may comprise less than about 47%, 45%, 43%, 40%, 38%, 35%, 33%, or 30% of the total amino acids of the extender peptide.

The aliphatic amino acids may comprise between about 20% and about 45% of the total amino acids of the extender peptide. The aliphatic amino acids may comprise between about 23% and about 45% of the total amino acids of the extender peptide. The aliphatic amino acids may comprise between about 23% and about 40% of the total amino acids of the extender peptide.

Aromatic amino acids may comprise less than about 20% of the total amino acids of the extender peptide. The aromatic amino acids may comprise less than about 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, or 10% of the total amino acids of the extender peptide. The aliphatic amino acids may comprise between 0% and about 20% of the total amino acids of the extender peptide.

The non-polar amino acids may comprise at least about 30% of the total amino acids of the extender peptide. The non-polar amino acids may comprise at least about 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% of the total amino acids of the extender peptide.

The non-polar amino acids may comprise at least about 32% of the total amino acids of the extender peptide. The non-polar amino acids may comprise less than about 80% of the total amino acids of the extender peptide. The non-polar amino acids may comprise less than about 77%, 75%, 72%, 70%, 69%, or 68% of the total amino acids of the extender peptide.

The non-polar amino acids may comprise between about 35% and about 80% of the total amino acids of the extender peptide. The non-polar amino acids may comprise between about 38% and about 80% of the total amino acids of the extender peptide. The non-polar amino acids may comprise between about 38% and about 75% of the total amino acids of the extender peptide. The non-polar amino acids may comprise between about 35% and about 70% of the total amino acids of the extender peptide.

The polar amino acids may comprise at least about 25% of the total amino acids of the extender peptide. The polar amino acids may comprise at least about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35% or more of the total amino acids of the extender peptide. The polar amino acids may comprise at least about 23% of the total amino acids of the extender peptide.

The polar amino acids may comprise less than about 80% of the total amino acids of the extender peptide. The polar amino acids may comprise less than about 77%, 75%, 72%, 70%, 69%, or 68% of the total amino acids of the extender peptide. The polar amino acids may comprise less than about 77% of the total amino acids of the extender peptide. The polar amino acids may comprise less than about 75% of the total amino acids of the extender peptide. The polar amino acids may comprise less than about 72% of the total amino acids of the extender peptide.

The polar amino acids may comprise between about 25% and about 70% of the total amino acids of the extender peptide. The polar amino acids may comprise between about 27% and about 70% of the total amino acids of the extender peptide. The polar amino acids may comprise between about 30% and about 70% of the total amino acids of the extender peptide.

Alternatively, the immunoglobulin fusion proteins disclosed herein do not include an extender peptide.

remedy

The immunoglobulin fusion proteins disclosed herein comprise one or more therapeutic agents. The therapeutic agent may be a peptide. The therapeutic agent may be a small molecule. The immunoglobulin fusion proteins disclosed herein may comprise two or more therapeutic agents. The immunoglobulin fusion proteins disclosed herein may comprise 3, 4, 5, 6 or more therapeutic agents. The two or more therapeutic agents may be the same. The two or more therapeutic agents may be different.

The therapeutic agent may comprise any secondary structure, eg, an alpha helix or a beta strand, or may not comprise a general secondary structure. The therapeutic agent comprises an amino acid having one or more modifications, said modifications being myristoylation, palmitoylation, isoprenylation, glypiation, lipoylation, acylation, acetylation, alkylation, methylation, glycosylation, Malonylation, hydroxylation, iodination, nucleotide addition, oxidation, phosphorylation, adenylation, propionylation, succinylation, sulfation, selenoylation, biotinylation, pegylation, deimination, deamidation , elimylation, and carbamylation. A therapeutic agent may comprise one or more small molecules, eg, one or more amino acids conjugated to a drug. In some embodiments, the therapeutic agent comprises one or more unnatural amino acids. In some embodiments, the therapeutic agent is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40 , 50 or more unnatural amino acids. In some embodiments, the therapeutic agent comprises one or more amino acid substitutions. In some embodiments, the therapeutic agent is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40 , containing 50 or more amino acid substitutions.

The therapeutic agent may be inserted into the immunoglobulin region. Insertion of a therapeutic agent into the immunoglobulin region may comprise removal or deletion of a portion of the immunoglobulin upon which the immunoglobulin region is based or derived. The therapeutic agent may substitute at least a portion of the heavy chain. The therapeutic agent may substitute at least a portion of the light chain. At least a portion of the variable domain may be substituted with a therapeutic agent. The therapeutic agent may substitute at least a portion of the constant domain. The therapeutic agent may replace at least a portion of the complementarity determining region (CDR). The therapeutic agent may substitute at least a portion of CDR1. The therapeutic agent may substitute at least a portion of CDR2. The therapeutic agent may substitute at least a portion of CDR3. At least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70 of the immunoglobulin or portion thereof with the therapeutic agent. %, 75%, 80%, 85%, 90%, 95% or more may be substituted.

The one or more therapeutic agents may be based on or derived from a protein. The protein may be a growth factor, cytokine, hormone or toxin. The growth factor may be GCSF, GMCSF, GDF11 or FGF21. The GCSF may be bovine GCSF. The GCSF may be human GCSF. The GMCSF may be bovine GMCSF or human GMCSF. FGF21 may be bovine FGF21. The FGF21 may be human FGF21. The protein may be elaffin. The protein may be a peptidase inhibitor. The protein may be skin derived antileukopretease (SKALP).

The cytokine may be an interferon or an interleukin. The cytokine may be stromal cell-derived factor 1 ( SDF -1). The interferon may be interferon-beta. The interferon may be interferon-alpha. The interleukin may be interleukin 11 (IL-11). The interleukin may be interleukin 8 (IL-8) or interleukin 21 (IL-21).

Hormones include exendin-4, GLP-1, relaxin, oxyntomodulin, hleptin, betatrophin, bovine growth hormone (bGH), human growth hormone (hGH), erythropoietin (EPO), or parathyroid hormone can be The hormone may be somatostatin. The parathyroid hormone may be human parathyroid hormone. The erythropoietin may be human erythropoietin.

The toxin may be Mocha 1, VM24 or Mamba 1. The toxin may be ziconotide or chlorotoxin. In one embodiment, the toxin is mu-SLPTX-Ssm6a (Ssam6).

The protein may be angiopoietin-like 3 (ANGPTL3). The angiopoietin-like 3 may be human angiopoietin-like 3.

The therapeutic agent may be glucagon-like peptide 2 (GLP2).

In some embodiments, the therapeutic agent is a glucagon analog.

In some embodiments, the therapeutic agent is a dual agent.

In some embodiments, one or more regions of the therapeutic agent are configured to treat diabetes and/or diabetes related conditions. In some embodiments, 2, 3, 4, 5 or more regions of the therapeutic agent are configured to treat diabetes and/or diabetes related conditions. Diabetes can include type I diabetes, type 2 diabetes, gestational diabetes, and prediabetes. In some embodiments, one or more regions of the therapeutic agent are configured to treat obesity and/or an obesity-related condition. In some embodiments, 2, 3, 4, 5 or more regions of the therapeutic agent are configured to treat obesity and/or an obesity related condition. Conditions may include complications and diseases. Examples of diabetes-related conditions may include, but are not limited to, diabetic retinopathy, diabetic kidney disease, diabetic heart disease, diabetic foot disorders, diabetic neuropathy, macrovascular disease, diabetic cardiomyopathy, infections and diabetic ketoacidosis. not limited Diabetic neuropathy may include, but is not limited to, symmetric polyneuropathy, autonomic neuropathy, neuromyopathy, cranial neuropathy, and mononeuropathy. Obesity-related conditions include heart disease, stroke, high blood pressure, diabetes, osteoarthritis, gout, sleep apnea, asthma, gallbladder disease, gallstones, abnormal blood fats (e.g., abnormal levels of LDL and HDL cholesterol), obesity, hypothyroidism syndrome, reproduction problems, hepatic steatosis, and psychological health conditions.

In some embodiments, the one or more regions of the therapeutic agent is a glucagon-like protein-1 (GLP-1) receptor agonist or an agent thereof. In some embodiments, one or more regions of the therapeutic agent are incretin mimetics. In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from the amino acid sequence of exendin-4, exenatide, or a compound thereof. In some embodiments, one or more regions of the therapeutic agent are glucagon analogs or formulations thereof. In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from the amino acid sequence of insulin. In some embodiments, one or more regions of the therapeutic agent are bispecific. In some embodiments, the therapeutic agent has specificity for a GLP-1 receptor and a glucagon receptor. In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from the amino acid sequence of oxyntomodulin.

In some embodiments, one or more regions of the therapeutic agent are configured to treat short bowel syndrome and/or a condition associated with short bowel syndrome. In some embodiments, 2, 3, 4, 5 or more regions of the therapeutic agent are configured to treat short bowel syndrome and/or short bowel syndrome related conditions. Short bowel syndrome related conditions may include, but are not limited to, bacterial overgrowth in the small intestine, metabolic acidosis, cholelithiasis, kidney stones, malnutrition, osteomalacia, intestinal abnormalities, and weight loss. In some embodiments, one or more regions of the therapeutic agent are configured to treat inflammatory bowel disease and/or inflammatory bowel related conditions. In some embodiments, 2, 3, 4, 5 or more regions of the therapeutic agent are configured to treat inflammatory bowel disease and/or inflammatory bowel related conditions. Inflammatory bowel disease and/or inflammatory bowel disease-related conditions include ulcerative colitis, Crohn's disease, collagen colitis, lymphocytic colitis, ischemic colitis, conversion colitis, Behcet's disease, metaphase colitis, anemia, arthritis, pyoderma gangrene, primary sclerosing cholangitis. , non-thyroid disease syndrome; and abdominal pain, vomiting, diarrhea, rectal bleeding, internal cramps or muscle cramps, and weight loss in individuals with inflammatory bowel disease.

In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from the amino acid sequence of glucagon, a glucagon analog, a glucagon-like peptide, and/or a glucagon-like peptide analog. In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from the amino acid sequence of glucagon-like peptide-2 (GLP2).

In some embodiments, one or more regions of the therapeutic agent are configured to treat an autoimmune disease and/or an autoimmune disease related condition. In some embodiments, 2, 3, 4, 5 or more regions of the therapeutic agent are configured to treat an autoimmune disease and/or an autoimmune disease related condition. Autoimmune diseases and/or autoimmune disease-associated conditions include acute disseminated encephalomyelitis, alopecia areata, antiphospholipid antibody syndrome, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, Autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Behcet’s disease, celiac disease, cold agglutininosis, Crohn’s disease, Dermatomyositis, type 1 diabetes, eosinophilic fasciitis, gastrointestinal pemphigoid, Goodpasture syndrome, Graves disease, Guillain-Barré syndrome, Hashimoto encephalopathy, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lupus erythematosus, Miller Fisher syndrome, mixed connective tissue disease , multiple sclerosis, myasthenia gravis, narcolepsy, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, relapsing polychondritis, rheumatoid arthritis, rheumatoid fever, Sjogren's syndrome, temporal arteritis, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, vasculitis, and Wegener's granulomatosis.

In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from an amino acid sequence that binds a potassium channel. In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from the amino acid sequence of mokatoxin-1 (Mocha).

In some embodiments, one or more regions of the therapeutic agent are configured to treat pain. In some embodiments, 2, 3, 4, 5 or more regions of the therapeutic agent are configured to treat pain.

In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from an amino acid sequence that is a neurotoxin. In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from the amino acid sequence of neurotoxin mu-SLPTX-Ssm6a (Ssam6). In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from the amino acid sequence of mambalgin-1.

In some embodiments, one or more regions of the therapeutic agent are configured to treat heart failure and/or fibrosis. In some embodiments, one or more regions of the therapeutic agent are configured to treat heart failure and/or fibrosis related conditions. In some embodiments, 2, 3, 4, 5 or more regions of the therapeutic agent are configured to treat heart failure and/or fibrosis. In some embodiments, 2, 3, 4, 5 or more regions of the therapeutic agent are configured to treat heart failure and/or fibrosis related conditions. Heart failure related conditions may include coronary heart disease, hypertension, diabetes, cardiomyopathy, heart valve disease, arrhythmias, congenital heart defects, obstructive sleep apnea, myocarditis, hyperthyroidism, hypothyroidism, emphysema, hemochromatosis and amyloidosis. The heart failure may be left heart failure, right heart failure, systolic heart failure, and diastolic heart failure. Fibrosis includes pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, liver cirrhosis, endocardial myocardial fibrosis, myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive mass fibrosis, renal systemic fibrosis, Crohn's disease, keloids, scleroderma/scleroderma, arthrofibrosis, Peyronie's disease, Dupuytren's contractures, and adhesive capsulitis.

In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from an amino acid sequence belonging to the insulin superfamily. In some embodiments, one or more regions of the therapeutic agent comprise an amino acid sequence that is based on or derived from the amino acid sequence of insulin.

In some embodiments, the amino acids of the therapeutic agent are based, in whole or in part, on or derived from any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 227-267. have. The therapeutic agent may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence that is at least about 50% identical to any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence that is at least about 70% identical to any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence that is at least about 80% identical to any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence that is 100% identical to any one of SEQ ID NOs: 227-267. In some embodiments, the therapeutic agent comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the amino acid sequence of any one of SEQ ID NOs: 227-267. , or an amino acid sequence that is 97% homologous. In some embodiments, the therapeutic agent comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the amino acid sequence of any one of SEQ ID NOs: 227-267. , or 97% identical amino acid sequences. In some embodiments, the therapeutic agent comprises an amino acid sequence that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 227-267.

The therapeutic agent may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids based on or derived from any one of SEQ ID NOs: 227-267. The therapeutic agent is 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 450, 500 based on or derived from any one of SEQ ID NOs: 227-267. It may include an amino acid sequence comprising more than one amino acid. The therapeutic agent may comprise an amino acid sequence comprising 10 or more amino acids based on or derived from any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence comprising 50 or more amino acids based on or derived from any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence comprising 100 or more amino acids based on or derived from any one of SEQ ID NOs: 227-267. The therapeutic agent may comprise an amino acid sequence comprising 200 or more amino acids based on or derived from any one of SEQ ID NOs: 227-267. The amino acids may be contiguous. Alternatively, or additionally, the amino acids may be discontinuous. In some embodiments, the therapeutic agent may comprise amino acids based on or derived from any one of SEQ ID NOs: 227-267 and amino acids not derived from any one of SEQ ID NOs: 227-267. In some embodiments, the therapeutic agent may comprise amino acids derived from one or more of SEQ ID NOs: 227-267 and amino acids not derived from any of SEQ ID NOs: 227-267. In some embodiments, the therapeutic agent comprises amino acids derived from 1, 2, 3, or 4 of SEQ ID NOs: 227-267.

The therapeutic agent may be encoded by a nucleic acid sequence based on or derived from any one of SEQ ID NOs: 186-226. The therapeutic agent may be encoded by a nucleic acid sequence that may be at least about 50% homologous to any one of SEQ ID NOs: 186-226. The therapeutic agent may be encoded by a nucleic acid sequence that may be at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to any one of SEQ ID NOs: 186-226. . The therapeutic agent may be encoded by a nucleic acid sequence that may be at least about 70% homologous to any one of SEQ ID NOs: 186-226. The therapeutic agent may be encoded by a nucleic acid sequence that may be at least about 80% homologous to any one of SEQ ID NOs: 186-226.

The therapeutic agent may comprise a protease cleavage site. A protease cleavage site may be inserted into a therapeutic agent. In some embodiments, the therapeutic agent comprises a first therapeutic agent region and a second therapeutic agent region. In some embodiments, the therapeutic agent comprises a protease cleavage site disposed between the first therapeutic agent region and the second therapeutic agent region. In some embodiments, the first therapeutic agent region and the second therapeutic agent region are derived from the same protein or the same set of amino acid sequences. In some embodiments, the first therapeutic agent region and the second therapeutic agent region are derived from different proteins or different sets of amino acid sequences. The one or more protease cleavage sites may be attached to the N-terminus, C-terminus or both N- and C-terminus of the therapeutic agent.

The therapeutic agent may comprise one or more internal linker peptides. The therapeutic agent may comprise two or more internal linker peptides. The therapeutic agent may comprise 3, 4, 5, 6, 7 or more internal linker peptides. The linker peptides may be different. The linker peptides may be identical. A linker peptide may be inserted into a therapeutic agent. In some embodiments, the therapeutic agent comprises a first therapeutic region, a second therapeutic region, one or more linker peptides disposed between the first and second therapeutic regions. The one or more linker peptides may be attached to the N-terminus, C-terminus or both N- and C-terminus of the therapeutic region. In some embodiments, the linker peptide is a protease cleavage site. In some embodiments, the linker peptide is a tag, eg, an affinity tag. An example of an affinity tag is the 6X(HHHHHH) histidine tag (SEQ ID NO: 274). In some embodiments, the internal linker comprises amino acids having repeat sequences. In some embodiments, the internal linker has 2, 3, 4, 5, 6, 7, 8, 9, 10 or more repeat sequences. In some embodiments, the internal linker is low in immunogenicity. In some embodiments, the internal linker is biodegradable.

The therapeutic agent may be inserted into the antibody region. Insertion of a therapeutic agent into an antibody region comprises the removal or deletion of one or more amino acids from the antibody region.

In some embodiments, the immunoglobulin fusion protein comprises one or more extender peptides. The one or more extender peptides may be attached to the N-terminus, C-terminus or both N- and C-terminus of the therapeutic agent.

In some embodiments, the immunoglobulin fusion protein comprises one or more linker peptides. One or more linkers may be attached to the N-terminus, C-terminus or both N- and C-terminus of the therapeutic agent.

In some embodiments, the immunoglobulin fusion protein comprises one or more proteolytic cleavage sites. The one or more proteolytic cleavage sites may be attached to the N-terminus, C-terminus or both N- and C-terminus of the therapeutic agent.

In some embodiments, a therapeutic agent may be linked to an antibody region without the aid of an extender peptide. The therapeutic agent may be linked to the antibody via one or more linkers.

linker

The immunoglobulin fusion protein, antibody region, non-antibody region and/or extender fusion region may further comprise one or more linkers. The immunoglobulin fusion protein, antibody region, non-antibody region and/or extender fusion region may further comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more linkers. The extender fusion region may further comprise one or more linkers. The extender fusion region may further comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more linkers.

One or more linkers are attached to the N-terminus, C-terminus or both N- and C-terminus of the therapeutic agent. One or more linkers are attached to the N-terminus, C-terminus or both N- and C-terminus of the extender peptide. One or more linkers are attached to the N-terminus, C-terminus or both N- and C-terminus of the proteolytic cleavage site. The one or more linkers may be attached to a therapeutic agent, an extender peptide, a proteolytic cleavage site, an extender fusion region, an antibody region, or a combination thereof.

In some embodiments, the linker peptide is a linking peptide or is part of a linking peptide.

The one or more linkers may comprise the sequence (X ^e X ^f X ^g X ^h ) _n (SEQ ID NO: 176). In one embodiment, n is between about 1 and about 20. In one embodiment n is any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In one embodiment, n is between about 1 and about 10. In one embodiment, n is between about 1 and about 5. In one embodiment, n is between about 1 and about 3. In one embodiment, X ^e , X ^f and X ^g are independently selected from hydrophobic amino acids. X ^h may be a polar, uncharged amino acid. The linker sequence may further comprise one or more cysteine (C) residues. The one or more cysteine residues are at the N-terminus, the C-terminus, or a combination thereof. The linker peptide may comprise the sequence CX ^e X ^f X ^g X ^h (SEQ ID NO: 177). In one embodiment, X ^e , X ^f and X ^g are independently selected from hydrophobic amino acids. X ^h may be a polar, uncharged amino acid. The linker peptide may comprise the sequence X ^e X ^f X ^g X ^h C (SEQ ID NO: 178). In one embodiment, X ^e , X ^f and X ^g are independently selected from hydrophobic amino acids. X ^h may be a polar, uncharged amino acid.

The one or more linkers may comprise the sequence (GGGGS) _n (SEQ ID NO: 275). In one embodiment, n is between about 1 and about 20. In one embodiment n is any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In one embodiment, n is between about 1 and about 10. In one embodiment, n is between about 1 and about 5. In one embodiment, n is between about 1 and about 3.

The one or more linkers may comprise an amino acid sequence selected from any one of SEQ ID NOs: 176, 179-181 and 275-277. The one or more linkers may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 176, 179-181 and 275-277. the one or more linkers are amino acids that are at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to any one of SEQ ID NOs: 176, 179-181 and 275-277 sequence may be included. The one or more linkers may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 176, 179-181 and 275-277. The one or more linkers may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 176, 179-181 and 275-277.

proteolytic cleavage site

The immunoglobulin fusion proteins disclosed herein may further comprise one or more proteolytic cleavage sites. The immunoglobulin fusion proteins disclosed herein may further comprise two or more proteolytic cleavage sites. The immunoglobulin fusion proteins disclosed herein may further comprise three or more proteolytic cleavage sites. The immunoglobulin fusion proteins disclosed herein may further comprise 4, 5, 6, 7 or more proteolytic cleavage sites. The therapeutic agents disclosed herein may further comprise one or more proteolytic cleavage sites.

An immunoglobulin fusion protein may comprise a sequence having one or more cleavage sites between the antibody region and the non-antibody region. The immunoglobulin fusion protein may comprise a sequence having one or more cleavage sites between the antibody region and the extender fusion region. In some embodiments, the proteolytic cleavage site is or is part of a linking peptide.

The one or more proteolytic cleavage sites may be attached to the N-terminus, C-terminus or both N- and C-terminus of the therapeutic peptide. The one or more proteolytic cleavage sites may be attached to the N-terminus, C-terminus or both N- and C-terminus of the extender peptide. The one or more proteolytic cleavage sites may be attached to the N-terminus, C-terminus or both N- and C-terminus of the linker peptide. The one or more proteolytic cleavage sites may be attached to a therapeutic peptide, extender peptide, linker, extender fusion region, immunoglobulin region, non-immunoglobulin region, or combinations thereof.

Cleavage of the proteolytic cleavage site may in turn liberate the N- or C-terminus of the therapeutic agent from the immunoglobulin fusion protein. Proteolytic cleavage sites may be present at the N- and C-terminus of the therapeutic agent. Cleavage of the proteolytic cleavage site may in turn liberate the therapeutic agent from the immunoglobulin fusion protein.

Alternatively, or additionally, the proteolytic cleavage site is located within the amino acid sequence of the therapeutic agent, extender peptide, antibody region, or combination thereof. A therapeutic agent may comprise one or more proteolytic cleavage sites within its amino acid sequence. For example, SEQ ID NO: 89 discloses a relaxin protein comprising two internal proteolytic cleavage sites. Cleavage of the proteolytic cleavage site in the relaxin protein may in turn liberate the internal fragment of the relaxin protein.

The two or more proteolytic cleavage sites may surround a therapeutic agent, extender peptide, linker, antibody region, or a combination thereof. Cleavage of the proteolytic cleavage site may in turn liberate peptide fragments located between two or more proteolytic cleavage sites. For example, a proteolytic cleavage site may be flanked by a therapeutic agent-linker peptide. Cleavage of the proteolytic cleavage site may in turn liberate the therapeutic agent-linker.

A proteolytic cleavage site may be recognized by one or more proteases. The one or more proteases may be serine proteases, threonine proteases, cysteine proteases, aspartate proteases, glutamic acid proteases, metalloproteases, exopeptidases, endopeptidases, or combinations thereof. The protease may be selected from the group comprising Factor VII or Factor Xa. Still other examples of proteases include, but are not limited to, aminopeptidase, carboxypeptidase, trypsin, chymotrypsin, pepsin, papain, and elastase. The protease may be prohormone convertase 2 (PC2).

The one or more proteolytic cleavage sites may comprise an amino acid sequence selected from any one of SEQ ID NOs: 182-185. The one or more proteolytic cleavage sites may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 182-185. the one or more proteolytic cleavage sites comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to any one of SEQ ID NOs: 182-185 can do. The one or more proteolytic cleavage sites may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 182-185. The one or more proteolytic cleavage sites may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 182-185.

Vectors, Host Cells and Recombinant Methods

The immunoglobulin fusion proteins disclosed herein can be expressed by recombinant methods. In general, a nucleic acid encoding an immunoglobulin fusion protein can be isolated and inserted into a replicable vector for further cloning (DNA amplification) or expression. DNA encoding the immunoglobulin fusion protein is prepared by PCR amplification and sequenced using conventional procedures (eg, using an oligonucleotide probe capable of binding specifically to nucleotides encoding the immunoglobulin fusion protein). can be In an exemplary embodiment, the nucleic acid encoding the immunoglobulin fusion protein is PCR amplified, restriction digested and gel purified. The cleaved nucleic acid can be inserted into a replicable vector. The replicable vector comprising the truncated immunoglobulin fusion protein insert can be transformed or transduced into a host cell for further cloning (DNA amplification) or expression. The host cell may be a prokaryotic or eukaryotic cell.

Polynucleotide sequences encoding polypeptide components (eg, antibody regions, extender peptides, therapeutic agents) of immunoglobulin fusion proteins can be obtained by PCR amplification. A polynucleotide sequence can be isolated and sequenced from a cell comprising a nucleic acid encoding a polypeptide component. Alternatively, or in addition, polynucleotides can be synthesized using nucleotide synthesizers or PCR techniques. Once obtained, the sequences encoding the polypeptide components can be inserted into a recombinant vector capable of replicating and expressing the heterologous polynucleotide in a prokaryotic or eukaryotic host.

In addition, phage vectors comprising replicon and regulatory sequences suitable for the host microorganism may be used as transformation vectors in connection with the host. For example, using a bacteriophage such as λGEM™-11, E. Recombinant vectors can be made that can be used to transform susceptible host cells such as E. coli LE392 .

Immunoglobulin fusion proteins can be expressed intracellularly (eg, cytoplasmic) or extracellularly (eg, secreted). For extracellular expression, the vector may contain a secretion signal capable of moving the immunoglobulin fusion protein out of the cell.

Suitable host cells for cloning or expression of an immunoglobulin fusion protein-encoding vector include prokaryotic or eukaryotic cells. The host cell may be a eukaryotic cell. Examples of eukaryotic cells include human embryonic kidney (HEK) cells, Chinese hamster ovary (CHO) cells, fungi, yeast, invertebrate cells (eg, plant and insect cells), lymphoid cells (eg, YO, NSO, Sp20). cells), but are not limited thereto. Other examples of suitable mammalian host cell lines include the SV40 transformed monkey kidney CV1 cell line (COS-7); baby hamster kidney cells (BHK); mouse Sertoli cells; monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK; Madin-Darby, canine kidney); buffalo rat liver cells (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumor (MMT 060562); TR1 cells; MRC 5 cells; and FS4 cells. The host cell may be a prokaryotic cell (eg, E. coli).

A host cell can be transformed with a vector comprising a nucleotide encoding an immunoglobulin fusion protein. Transformed host cells can be cultured in a medium. The medium may be supplemented with one or more agents for inducing a promoter, selecting transformants, or amplifying or expressing a gene encoding a desired sequence. Methods for transformation of host cells are known in the art and may include electroporation, calcium chloride, or polyethylene glycol/DMSO methods.

Alternatively, the host cell may be transfected or transduced with a vector comprising nucleotides encoding an immunoglobulin fusion protein. The transfected or transduced host cells may be cultured in a medium. The medium may be supplemented with one or more agents for inducing a promoter, selecting for transfected or transduced cells, or for expressing a gene encoding a desired sequence.

A host cell may be transfected or transduced with a vector comprising nucleotides encoding one or more proteases. A vector comprising a protease may be co-transfected with a vector encoding any of the immunoglobulin fusion proteins disclosed herein. Proteases include factors Xa and PC2.

The expressed immunoglobulin fusion protein can be secreted into the periplasm of the host cell and recovered therefrom or transported to the culture medium. Protein recovery from the periplasm may involve disrupting the host cell. The step of disrupting the host cell may include osmotic shock, sonication, or lysis. Centrifugation or filtration can be used to remove cell debris or whole cells. The immunoglobulin fusion protein can be further purified, for example, by affinity resin chromatography.

Alternatively, immunoglobulin fusion proteins secreted into the culture medium can be isolated therein. The medium supernatant can be concentrated by filtration to remove cells from the medium and further purify the protein produced. The expressed polypeptide can be further isolated and identified using commonly known methods such as polyacrylamide gel electrophoresis (PAGE) and Western blot analysis.

Immunoglobulin fusion proteins can be produced in large quantities by fermentation processes. A large variety of fed-batch fermentation methods are available for recombinant protein production. Large-scale fermentations have a capacity of at least 1000 liters, preferably about 1,000 to 100,000 liters. These fermentors use agitator impellers to distribute oxygen and nutrients, particularly glucose (the preferred carbon/energy source). Small scale expression refers to fermentation in a fermentor having a volume of approximately 100 liters or less, and may range from about 1 liter to about 100 liters.

In a fermentation process, induction of protein expression is usually initiated after the cells are incubated under suitable conditions to a desired density, eg, an OD550 of about 180-220 at a stage in which the cells are in an initial stationary phase. A variety of inducers can be used depending on the vector construct, as known in the art and described herein. Cells may be cultured for a shorter period prior to induction. Although longer or shorter induction times can be used, cells are usually induced for about 12-50 hours.

To improve the production yield and quality of the immunoglobulin fusion proteins disclosed herein, several fermentation conditions can be adjusted. For example, to enhance proper assembly and folding of secreted immunoglobulin fusion protein polypeptides, chaperone proteins, such as Dsb proteins (DsbA, DsbB, DsbC, DsbD and/or DsbG) or FkpA (peptides with chaperone activity) Additional vectors overexpressing dilprolyl cis,trans-isomerase) can be used to co-transfect host prokaryotic cells. Chaperone proteins have been demonstrated to promote proper folding and solubility of heterologous proteins produced in bacterial host cells.

To minimize proteolysis of expressed heterologous proteins (especially those susceptible to proteolysis), certain host strains deficient in proteolytic enzymes can be used in the present disclosure. For example, the host cell strain may contain genetic variation(s) in genes encoding known bacterial proteases, e.g., Protease III, OmpT, DegP, Tsp, Protease I, Protease Mi, Protease V, Protease VI, and combinations thereof. It can be transformed to bring Some E. coli protease deficient strains are available.

Standard protein purification methods known in the art can be used. The following procedures are suitable representative purification procedures: fractionation on immunoaffinity or ion exchange columns, ethanol precipitation, reverse phase HPLC, silica chromatography or cation exchange resin chromatography such as DEAE, chromatofocusing, SDS-PAGE, ammonium sulfate precipitation, oxalic acid Apatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, and gel filtration using, for example, Sephadex G-75.

Immunoglobulin fusion proteins can be concentrated using a commercially available protein concentration filter, such as an Amicon or Millipore Pellicon ^® ultrafiltration unit.

A protease inhibitor or cocktail of protease inhibitors may be included in any of the above steps to inhibit proteolysis of the immunoglobulin fusion protein.

In some instances, the immunoglobulin fusion protein may not be biologically active when isolated. Several methods of "refolding" or "converting" a polypeptide to its tertiary structure and generating disulfide bonds can be used to restore biological activity. Such methods include exposing the solubilized polypeptide to the presence of a specific concentration of chaotrope and a pH usually greater than 7. The selection method for chaotropes is very similar to the selection method used for inclusion body solubilization, however, chaotropes are usually used at lower concentrations and are not necessarily identical to the chaotropes used for solubilization. In most cases, the refolding/oxidation solution will also contain a reducing agent or reducing agent and its oxidized form in specific proportions to create a specific redox potential, which will enable disulfide shuffling to form the cysteine bridge(s) of the protein . Some commonly used redox couples include cysteine/cystamine, glutathione (GSH)/dithiobis GSH, cupric chloride, dithiothreitol (DTT)/dithiane DTT, and 2-mercaptoethanol (bME)/di -thio-b(ME) is included. In many cases, a cosolvent can be used to increase the efficiency of refolding, and typical reagents used for this purpose include glycerol, polyethylene glycols of various molecular weights, arginine, and the like.

composition

Disclosed herein are compositions comprising the immunoglobulin fusion proteins disclosed herein and/or components of the immunoglobulin fusion proteins disclosed herein. The composition may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more immunoglobulin fusion proteins. The immunoglobulin fusion proteins may be different. Alternatively, the immunoglobulin fusion proteins may be identical or similar. The immunoglobulin fusion protein may comprise different antibody regions, extender fusion regions, extender peptides, therapeutic agents, or combinations thereof.

The composition may further comprise one or more pharmaceutically acceptable salts, excipients or vehicles. Pharmaceutically acceptable salts, excipients, or vehicles for use in the pharmaceutical compositions include carriers, excipients, diluents, antioxidants, preservatives, coloring agents, flavoring and diluents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, tonicity agents, cosolvents, wetting agents, complexing agents, buffers, antibacterial agents, and surfactants.

Neutral buffered saline or saline mixed with serum albumin are typically suitable carriers. The pharmaceutical composition may contain an antioxidant such as ascorbic acid; low molecular weight polypeptide proteins such as serum albumin, gelatin, or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt forming counterions such as sodium; and/or nonionic surfactants such as Tween, pluronics, or polyethylene glycol (PEG). Also, by way of example, suitable tonicity enhancing agents include alkali metal halides (preferably sodium or potassium chloride), mannitol, sorbitol, and the like. Suitable preservatives include benzalkonium chloride, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, and the like. In addition, hydrogen peroxide can be used as a preservative. Suitable cosolvents include glycerin, propylene glycol, and PEG. Suitable complexing agents include caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxy-propyl-beta-cyclodextrin. Suitable surfactants or wetting agents include sorbitan esters, polysorbates such as polysorbate 80, tromethamine, lecithin, cholesterol, tyloxapal, and the like. The buffer may be a conventional buffer, for example, acetate, borate, citrate, phosphate, bicarbonate, or Tris-HCl. The acetate buffer may be about pH 4-5.5, and the Tris buffer may be about pH 7-8.5. Additional pharmaceutical formulations are presented in Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed., Mack Publishing Company, 1990.

The composition may be in liquid form or lyophilized form and may contain one or more cryoprotectants, excipients, surfactants, high molecular weight structural additives, and/or bulking agents (eg, US Pat. Nos. 6,685,940, 6,566,329, and 6,372,716). see) may be included. In one embodiment, the cryoprotectant comprises a non-reducing sugar such as sucrose, lactose or trehalose. The amount of cryoprotectant is generally included so that upon reconstitution the resulting formulation is isotonic, although high or slightly hypotonic formulations may also be suitable. In addition, the amount of cryoprotectant should be sufficient to prevent degradation and/or aggregation of unacceptable amounts of protein upon lyophilization. For sugars (eg, sucrose, lactose, trehalose) in pre-lyophilized formulations, typical cryoprotectant concentrations are from about 10 mM to about 400 mM. In another embodiment, surfactants include, for example, nonionic surfactants and ionic surfactants such as polysorbates (eg polysorbate 20, polysorbate 80); poloxamers (eg, poloxamer 188); poly(ethylene glycol) phenyl ethers (eg, Triton); sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-myristyl-linoleyl- or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; lauryl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (eg, lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl opeyl-taurate; MonaQUAT™ series (Mona Industries, Inc., Paterson, NJ), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (eg Pluronics , PF68, etc.). A typical amount of surfactant that may be present in a pre-lyophilized formulation is about 0.001-0.5%. High molecular weight structural additives (eg fillers, binders) can be, for example, acacia, albumin, alginic acid, calcium phosphate (dibasic), cellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose , hydroxypropylmethylcellulose, microcrystalline cellulose, dextran, dextrin, dextrate, sucrose, tylose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, disodium hydrogen phosphate, Disodium phosphate, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, liquid glucose, compressible sugar, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polymethacrylate, povidone, sodium alginate, tragacanth undecided vaginal cellulose, starch, and zein. Typical concentrations of high molecular weight structural additives are between 0.1% and 10% by weight. In other embodiments, bulking agents (eg, mannitol, glycine) may be included.

The composition may be suitable for parenteral administration. Exemplary compositions may be administered in any route available to the skilled artisan, for example, intra-articular, subcutaneous, intravenous, intramuscular, intraperitoneal, intracerebral (intraventricular), intraventricular, intramuscular, intraocular, intraarterial, or intralesional routes. suitable for injection or infusion into animals by Parenteral formulations may typically be a sterile, pyrogen-free isotonic aqueous solution optionally containing a pharmaceutically acceptable preservative.

Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Linker's dextrose, dextrose and sodium chloride, lactated Ringer's solution, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on linker dextrose, and the like. In addition, preservatives and other additives may be present, such as antibacterial agents, antioxidants, chelating agents, inert gases, and the like. In general, reference is made to Remington's Pharmaceutical Science, 16th Ed., Mack Eds., 1980.

The compositions disclosed herein may be formulated for controlled or sustained delivery in a manner that provides a local concentration (eg , bolus, depot effect) and/or increased stability or half-life of the product in a particular topical environment. The composition comprises biodegradable matrices, injectable microspheres, microcapsule particles, microcapsules, as well as particulate formulations of polymeric compounds such as polylactic acid, polyglycolic acid that provide controlled or sustained release of an active agent that can then be delivered by depot injection. , biodegradable particle beads, liposomes, and formulations of the immunoglobulin fusion proteins, polypeptides, nucleic acids, or vectors disclosed herein using agents such as implantable delivery devices. The formulation technology of such sustained or controlled delivery means is known, and various polymers have been developed and used for controlled release and delivery of drugs. Such polymers are typically biodegradable and biocompatible. Polymeric hydrogels, including those formed by complex formation of enantiomeric polymers or polypeptide fragments and hydrogels that are sensitive to temperature or pH, provide a drug depot effect due to the weak aqueous conditions involved in trapping bioactive protein agents. may be desirable. See, for example, the description of controlled release porous polymeric microparticles for the delivery of pharmaceutical compositions in WO93/15722.

Materials suitable for this purpose include polylactide (see, eg, US Pat. No. 3,773,919), polymers of poly-(a-hydroxycarboxylic acid), such as poly-D-(-)-3-hydroxybutyric acid. (EP 133,988A), a copolymer of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al. , Biopolymers, 22: 547-556 (1983)), poly(2-hydroxyethyl-methacrylate) ( Langer et al. , J. Biomed. Mater. Res., 15: 167-277 (1981), and Langer, Chem. Tech., 12: 98-105 (1982)), ethylene vinyl acetate, or poly-D ( -)-3-hydroxybutyric acid. Other biodegradable polymers include poly(lactones), poly(acetals), poly(orthoesters), and poly(orthocarbonates). Sustained release compositions may also include liposomes, which may be prepared by a number of methods known in the art (see, e.g., Eppstein et al. , Proc. Natl. Acad. Sci. USA, 82: 3688). -92 (1985)).The carrier itself, or its degradation products, must be non-toxic in the target tissue and must not exacerbate the condition.It is an animal model of the target disorder, or, if this model is not possible, in a normal animal. It can be determined by routine screening.

The immunoglobulin fusion proteins disclosed herein may be microencapsulated.

The pharmaceutical compositions disclosed herein may be administered by any suitable route of administration, including parenteral (intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intravitreal, infusion, or topical), transdermal including, but not limited to, topical, oral, or nasal administration.

Formulations suitable for intramuscular, subcutaneous, peritumoral, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. have. Examples of aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene-glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (eg olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity is maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersants, and by the use of surfactants. Formulations suitable for subcutaneous injection also optionally contain additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents.

For intravenous injection, the active agent is optionally formulated in an aqueous solution, preferably in a physiologically compatible buffer such as Hanks' solution, Ringer's solution, or physiological saline buffer.

Parenteral injections optionally involve bolus injections or continuous infusions. Formulations for injection are provided in unit dosage form, eg, in ampoules or in multi-dose containers, optionally with an added preservative. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active agents in water-soluble form. Additionally, suspensions are optionally prepared as suitable oily injection suspensions.

Alternatively, or in addition, the compositions may be administered topically via implantation of a membrane, sponge, or other suitable material into the affected area into which the immunoglobulin fusion proteins disclosed herein are absorbed or encapsulated. When an implantable device is used, the device may be implanted in any suitable tissue or organ, and the immunoglobulin fusion proteins, nucleic acids, or vectors disclosed herein may be administered directly via a catheter using a bolus, or continuous administration, or continuous infusion. can be transmitted.

A pharmaceutical composition comprising an immunoglobulin fusion protein disclosed herein may be formulated for inhalation, eg, as a dry powder. Inhalation liquids may also be formulated in liquefied propellants for aerosol delivery. In another formulation, the solution may be nebulized. Another pharmaceutical composition for pulmonary administration includes, for example, those described in WO 94/20069 which discloses pulmonary delivery of chemically modified proteins. For pulmonary delivery, the particle size should be suitable for delivery to the lung terminal. For example, the particle size may be between 1 μm and 5 μm. However, larger particles may be used if each particle is appropriately porous.

Certain formulations comprising the immunoglobulin fusion proteins disclosed herein can be administered orally. Formulations administered by this method may be formulated with or without carriers conventionally used to formulate solid dosage forms, such as tablets and capsules. For example, the capsule may be designed to release the active portion of the formulation at a point in the gastrointestinal tract where bioavailability is maximized and degradation prior to systemic circulation is minimized. Additives may be included to facilitate absorption of the optional binder. In addition, diluents, flavoring agents, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders may be employed.

Another formulation may involve an effective amount of an immunoglobulin fusion protein admixed with a non-toxic excipient suitable for the manufacture of tablets. Solutions can be prepared in unit dosage form by dissolving the tablets in sterile water, or another suitable vehicle. Suitable excipients include inert diluents such as calcium carbonate, sodium carbonate or sodium bicarbonate, lactose, or calcium phosphate; or binders such as starch, gelatin or acacia; or lubricants such as magnesium stearate, stearic acid, or talc.

Suitable and/or preferred pharmaceutical formulations can be determined in light of the present disclosure and general knowledge of formulation technology, depending on the desired route of administration, mode of delivery, and desired dosage. Regardless of the method of administration, the effective amount can be calculated according to the weight, body surface area, or organ size of the patient.

Further refinement of the calculated values to determine an appropriate dosage for treatment involving each of the formulations described herein is routinely made in the art and is within the scope of work routinely performed in the art. Suitable dosages can be ascertained using suitable dose response data.

The compositions disclosed herein may be useful for providing a diagnosis or providing diagnostic information.

"Pharmaceutically acceptable" may indicate that it has been approved or is acceptable by a federal or state regulatory agency or is listed in the United States Pharmacopoeia or other commonly recognized pharmacopeia for use in animals, including humans.

"Pharmaceutically acceptable salt" may refer to a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound.

A “pharmaceutically acceptable excipient, carrier or adjuvant” can be administered to a subject in association with at least one antibody of the present disclosure without destroying its pharmacological activity when administered in a dose sufficient to deliver a therapeutic amount of the compound. non-toxic excipients, carriers or adjuvants.

A “pharmaceutically acceptable vehicle” may refer to a diluent, adjuvant, excipient, or carrier with which at least one antibody of the present disclosure is administered.

kit

Also disclosed herein are kits comprising one or more immunoglobulin fusion proteins or components thereof. Immunoglobulin fusion proteins can be packaged in a manner that facilitates their use in practicing the methods of the present disclosure. For example, the kit comprises an immunoglobulin fusion protein described herein packaged in a container and a label or package insert affixed to the container explaining the use of the immunoglobulin fusion protein in practicing the methods. Suitable containers include, for example, bottles, vials, syringes, and the like. The container may be made of a variety of materials, such as glass or plastic. The container may have a sterile access port (eg the container may be an intravenous solution bag or vial with a stopper pierceable with a hypodermic injection needle). A kit may include a container having an immunoglobulin fusion protein contained therein. The kit comprises (a) an antibody region of an immunoglobulin fusion protein; (b) an extender fusion region of an immunoglobulin fusion protein; (c) an extender peptide of the extender fusion region; (d) a therapeutic agent of the extender fusion region; or (e) a container comprising a combination of a-d. The kit may further comprise a package insert indicating that the first and second compositions may be used to treat a particular condition. Alternatively, or additionally, the kit further comprises a second (or third) container comprising a pharmaceutically acceptable buffer (eg, bacteriostatic water for injection (BWFI), phosphate buffered saline, linker solution, and dextrose solution). may include The kit may further include other materials that are commercial and desirable from a user standpoint, including, but not limited to, other buffers, diluents, fillers, needles and syringes. The immunoglobulin fusion protein may be packaged in unit dosage form. The kit may further include a device suitable for administering the immunoglobulin fusion protein or performing a screening assay according to a particular route of administration. The kit may include a label explaining the use of the immunoglobulin fusion protein composition.

Compositions comprising immunoglobulin fusion proteins may be formulated according to conventional procedures as pharmaceutical compositions adapted for intravenous administration to mammals, such as humans, cows, cats, dogs, and mice. Typically, compositions for intravenous administration include solutions in sterile isotonic aqueous buffer. If desired, the composition may also contain a solubilizing agent and/or a local anesthetic to relieve pain at the injection site, for example lignocaine. In general, the components may be presented individually or mixed together in unit dosage form. For example, the immunoglobulin fusion protein can be provided as a lyophilized powder or water-free concentrate in a sealed container such as an ampoule or sachet indicating the amount of the immunoglobulin fusion protein. When the composition is administered by infusion, it may be dispensed with an infusion bottle containing sterile pharmaceutical grade water or sterile saline. When the composition is administered by injection, an ampoule of sterile water for injection or saline may be provided so that the components can be mixed before administration.

The amount of a composition described herein that will be effective in the treatment, inhibition and/or prevention of a disease or disorder associated with aberrant expression and/or activity of a therapeutic agent can be determined by standard clinical techniques. In addition, in vitro assays can optionally be used to help identify optimal dosage ranges. The exact dosage employed in the formulation may also depend on the route of administration, and the severity of the disease or disorder, and should be determined according to the judgment of the physician and each patient's circumstances. Effective dosages can be extrapolated from dose response curves derived from in vitro animal model test systems or clinical trials.

therapeutic use

Also disclosed herein are immunoglobulin fusion proteins for methods of treating, ameliorating, inhibiting and/or preventing one or more diseases and/or conditions. The methods may comprise administering to a subject in need thereof a composition comprising one or more immunoglobulin fusion proteins disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. In some cases, an immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The non-antibody region comprises one or more therapeutic agents. The extender fusion region comprises one or more therapeutic agents. In some embodiments, the non-immunoglobulin region comprises one or more extender peptides. In some embodiments, the extender fusion region comprises one or more extender peptides. In one embodiment, the extender peptide comprises an amino acid sequence having a secondary structure of an alpha helix. In one embodiment, the extender peptide does not comprise an amino acid sequence having a secondary structure of the beta strand. In some embodiments, the non-immunoglobulin region comprises one or more linker peptides. In some embodiments, the extender fusion region comprises one or more linker peptides. In one embodiment, the linker peptide does not comprise sequencing of amino acids having secondary structures of alpha helices or beta strands.

The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal is a cow. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. Therapeutic agents include GCSF, bovine GCSF, human GCSF, Mocha 1, Vm24, Mamba 1, human GLP-1, exendin-4, human EPO, human FGF21, human GMCSF, human interferon-beta, human interferon-alpha, relaxin, oxyntomodulin, hleptin, betatrophin, growth differentiation factor 11 (GDF11), parathyroid hormone, angiopoietin-like 3 (ANGPTL3), IL-11, human growth hormone (hGH), elafin or derivatives thereof; It may be a variant. Alternatively, or in addition, the therapeutic agent is interleukin 8 (IL-8), IL-21, ziconotide, somatostatin, chlorotoxin, SDF1 alpha or a derivative or variant thereof. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The disease or condition may be an autoimmune disease, a heteroimmune disease or condition, an inflammatory disease, a pathogenic infection, a thromboembolic disorder, a respiratory disease or condition, a metabolic disease, a central nervous system (CNS) disorder, a bone disease, or cancer. In other instances, the disease or condition is a blood disorder. In some instances, the disease or condition is obesity, diabetes, osteoporosis, anemia, or pain. The therapeutic agent may be hGCSF and the disease or condition may be neutropenia. The therapeutic agent may be hleptin and the disease or condition may be diabetes. The therapeutic agent may be hGH and the disease or condition may be a growth disorder. The therapeutic agent may be IFN-alpha and the disease or condition may be a viral infection. The therapeutic agent may be Mamba 1 and the disease or condition may be pain. The therapeutic agent may be elafin and the disease or condition may be inflammation. The therapeutic agent may be IFN-alpha and the disease or condition may be an elastase inhibitor peptide and the disease or condition may be chronic obstructive pulmonary disease (COPD).

The disease and/or condition may be a chronic disease or condition. Alternatively, the disease and/or condition is an acute disease or condition. The disease or condition may be relapsing, refractory, accelerated or remission. A disease or condition may affect more than one cell type. The one or more diseases and/or conditions may be autoimmune diseases, inflammatory diseases, cardiovascular diseases, metabolic disorders, pregnancy, and cytoproliferative disorders.

The disease or condition may be an autoimmune disease. In some instances, the autoimmune disease may be sclerosis, diffuse scleroderma, or systemic scleroderma.

The disease or condition may be an inflammatory disease. In some cases, the inflammatory disease may be hepatitis, fibromyalgia or psoriasis.

The disease or condition may be a rheumatic disease. In some cases, the rheumatoid disease is ankylosing spondylitis, back pain, bursitis, tendinitis, shoulder pain, wrist pain, biceps pain, leg pain, knee pain, ankle pain, hip pain, Achilles pain, capsulitis, neck pain, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, juvenile arthritis, Schaegren's syndrome, polymyositis, Behcet's disease, Reiter's syndrome, or psoriatic arthritis. The rheumatic disease may be chronic. Alternatively, the rheumatic disease is acute.

The disease or condition may be a cardiovascular disease. In some instances, the cardiovascular disease may be acute heart failure, congestive heart failure, compensated heart failure, decompensated heart failure, hypercholesterolemia, atherosclerosis, coronary heart disease, or ischemic stroke. The cardiovascular disease may be cardiac hypertrophy.

The disease or condition may be a metabolic disorder. In some cases, metabolic disorders include hypercholesterolemia, hypobetalipoproteinemia, hypertriglyceridemia, hyperlipidemia, dyslipidemia, ketosis, hypolipidemia, intractable anemia, appetite control, gastric emptying, nonalcoholic fatty liver disease, obesity, 1 It can be type diabetes, type 2 diabetes, gestational diabetes, metabolic syndrome. The metabolic disorder may be type 1 diabetes. The metabolic disorder may be type 2 diabetes.

The disease or condition may be pregnancy. Immunoglobulin fusion proteins can be used to treat preeclampsia or to induce labor.

The disease or condition may be a cell proliferative disorder. The cell proliferative disorder may be a leukemia, a lymphoma, a carcinoma, a sarcoma, or a combination thereof. Cytoproliferative disorders include myelogenous leukemia, lymphoblastic leukemia, myeloid leukemia, myelomonocytic leukemia, neutrophilic leukemia, myelodysplastic syndrome, B-cell lymphoma, Burkitt's lymphoma, large-cell lymphoma, mixed cell lymphoma, follicular Sexual lymphoma, mantle cell lymphoma, Hodgkin's lymphoma, recurrent small lymphocyte lymphoma, hairy cell leukemia, multiple myeloma, basophil leukemia, eosinophilic leukemia, megaloblastic leukemia, mononuclear leukemia, monocytic leukemia, erythroleukemia , erythroid leukemia, hepatocellular carcinoma, solid tumors, lymphoma, leukemia, liposarcoma (advanced/metastasis), bone marrow malignancy, breast cancer, lung cancer, ovarian cancer, uterine cancer, kidney cancer, pancreatic cancer and malignant cranial glioma.

Disclosed herein is a method of treating a disease or condition in a subject in need thereof comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region comprising a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region comprising a therapeutic agent. In one embodiment, the therapeutic agent is oxyntomodulin. The disease or condition may be a metabolic disorder. The metabolic disorder may be diabetes. The diabetes may be type 2 diabetes. The diabetes may be type 1 diabetes. The metabolic disorder may be obesity. Another metabolic disorder includes, but is not limited to, metabolic syndrome, appetite control or gastric emptying.

Disclosed herein is a method of treating a disease or condition in a subject in need thereof comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region comprising a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region comprising a therapeutic agent. In one embodiment, the therapeutic agent is relaxin. The disease or condition may be a cardiovascular disease. The cardiovascular disease may be acute heart failure. Another cardiovascular disease includes, but is not limited to, congestive heart failure, compensated heart failure, or decompensated heart failure. The disease or condition may be an autoimmune disorder. The autoimmune disorder may be scleroderma, diffuse scleroderma, or systemic scleroderma. The disease or condition may be an inflammatory disease. The inflammatory disease may be fibromyalgia. The disease or condition may be fibrosis. Alternatively, the disease or condition is pregnancy. Immunoglobulin fusion proteins can be used to treat preeclampsia or to induce labor.

Disclosed herein is a method of treating a disease or condition in a subject in need thereof comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region comprising a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region comprising a therapeutic agent. In one embodiment, the therapeutic agent is beta-tropine. The disease or condition may be a metabolic disorder. The metabolic disorder may be obesity. Alternatively, the metabolic disorder is diabetes. The diabetes may be type 1 diabetes or type 2 diabetes.

Disclosed herein is a method of treating a disease or condition in a subject in need thereof comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region comprising a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region comprising a therapeutic agent. In one embodiment, the therapeutic agent is FGF 21. The disease or condition may be a metabolic disorder. The metabolic disorder may be obesity. The metabolic disorder may be diabetes. The diabetes may be type 2 diabetes, type 1 diabetes or gestational diabetes. Other metabolic disorders include, but are not limited to, appetite control and nonalcoholic fatty liver disease. The disease or condition may be a cell proliferative disorder. The cell proliferative disorder may be breast cancer.

Disclosed herein is a method of treating a disease or condition in a subject in need thereof comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region comprising a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region comprising a therapeutic agent. In one embodiment, the therapeutic agent is GDF11. The disease or condition may be a cell proliferative disorder. The cell proliferative disorder may be acute, chronic, relapsing, refractory, accelerated, remission, stage I, stage II, stage III, stage IV, juvenile or adult. Cytoproliferative disorders include myelogenous leukemia, lymphoblastic leukemia, myeloid leukemia, myelomonocytic leukemia, neutrophilic leukemia, myelodysplastic syndrome, B-cell lymphoma, Burkitt's lymphoma, large-cell lymphoma, mixed cell lymphoma, follicular Sexual lymphoma, mantle cell lymphoma, Hodgkin's lymphoma, recurrent small lymphocyte lymphoma, hairy cell leukemia, multiple myeloma, basophil leukemia, eosinophilic leukemia, megaloblastic leukemia, mononuclear leukemia, monocytic leukemia, erythroleukemia , erythroid leukemia, hepatocellular carcinoma, solid tumors, lymphoma, leukemia, liposarcoma (advanced/metastasis), myeloid malignancy, breast cancer, lung cancer, ovarian cancer, uterine cancer, kidney cancer, pancreatic cancer, and malignant cranial glioma. The disease or condition may be a cardiovascular disease. The cardiovascular disease may be an age-related heart disease. The disease or condition may be cardiac hypertrophy.

Disclosed herein is a method of treating a disease or condition in a subject in need thereof comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region comprising a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region comprising a therapeutic agent. In one embodiment, the therapeutic agent is angiopoietin like 3. The metabolic disorder may be hypercholesterolemia, hypobetalipoproteinemia, hypertriglyceridemia, hyperlipidemia, dyslipidemia, hypolipidemia or ketosis. The disease or condition may be a cardiovascular disease. The cardiovascular disease may be atherosclerosis, coronary heart disease or ischemic stroke. The disease or condition may be a rheumatic disease. Rheumatoid diseases include ankylosing spondylitis, back pain, bursitis, tendinitis, shoulder pain, wrist pain, biceps pain, leg pain, knee (patella) pain, ankle pain, hip pain, Achilles pain, capsulitis, neck pain, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, juvenile arthritis, Schaegren's syndrome, scleroderma, polymyositis, Behcet's disease, Reiter's syndrome, psoriatic arthritis. In some instances, the disease or condition may be a cell proliferative disorder. The cell proliferative disorder may be hepatocellular carcinoma or ovarian cancer. The disease or condition may be an inflammatory disease. The inflammatory disease may be hepatitis.

Disclosed herein is a method of preventing or treating a disease or condition in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. do. An immunoglobulin fusion protein may comprise one or more immunoglobulin heavy chains, light chains, or combinations thereof.

The immunoglobulin fusion protein has an amino acid sequence of any one of SEQ ID NOs: 68-99, and 122-143 and at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99% amino acid sequence. sequences that share identity. The nucleotide sequence encoding the immunoglobulin fusion protein comprises a nucleotide sequence of any one of SEQ ID NOs: 37-67, and 100-121 and 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, sequences that share at least 99% nucleotide sequence identity.

The immunoglobulin fusion protein has a heavy chain sequence provided by SEQ ID NOs: 69-79, 81-93, 95-97, 99, and 123-143 and 50%, 60%, 70%, 80%, 85%, 90%, sequences that share 95%, 97%, 99% or more amino acid sequence identity. The antibody region may comprise an immunoglobulin heavy chain. The immunoglobulin heavy chain polypeptide has a heavy chain sequence provided by SEQ ID NOs: 22-27 and 29-35 and at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99% amino acid sequence sequences that share identity. The antibody region may comprise an immunoglobulin light chain.

The immunoglobulin fusion protein comprises 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99% of the light chain sequence provided by SEQ ID NOs: 68, 80, 94, 98, and 122. It may include sequences that share more than one amino acid sequence identity. The antibody region may comprise an immunoglobulin light chain. The immunoglobulin light chain polypeptide has a light chain sequence provided by SEQ ID NOs: 19-21, 28 and 36 and at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99% amino acid sequence sequences that share identity. The antibody region may comprise an immunoglobulin heavy chain.

The immunoglobulin fusion protein has at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99% or more of the nucleotide sequence of any one of SEQ ID NOs: 68-99, and 122-143. may be encoded by homologous nucleotide sequences. The immunoglobulin heavy chain comprises SEQ ID NOs: 22-27, 29-35, 69-79, 81-93, 95-97, 99, and 123-143 and at least about 50%, 60%, 70%, 80%, 85%; It may be encoded by a nucleotide sequence that is at least 90%, 95%, 97%, 99% homologous. The immunoglobulin light chain comprises SEQ ID NOs: 19-21, 28, 36, 68, 80, 94, 98, and 122 and at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97% , which can be encoded by nucleotide sequences that are at least 99% homologous.

The immunoglobulin fusion protein may comprise one or more extender peptides. An immunoglobulin fusion protein may comprise one or more linkers. The immunoglobulin fusion protein may comprise one or more proteolytic cleavage sites. The disease or condition may be an autoimmune disease, a heteroimmune disease or condition, an inflammatory disease, a pathogenic infection, a thromboembolic disorder, a respiratory disease or condition, a metabolic disease, a central nervous system (CNS) disorder, a bone disease or cancer. The disease or condition may be a blood disorder. In some instances, the disease or condition may be obesity, diabetes, osteoporosis, anemia, or pain.

Disclosed herein is a method of preventing or treating an autoimmune disease in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. do. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on (a) an amino acid comprising an alpha helix and (i) an extra-long CDR3 based on or derived from seven an extender peptide comprising an amino acid sequence comprising the following amino acids or (ii) an amino acid sequence not comprising a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be Mocha 1 or a derivative or variant thereof. The therapeutic agent may be VM24 or a derivative or variant thereof. The therapeutic agent may be beta-interferon or a derivative or variant thereof. An immunoglobulin fusion protein or antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. The mammalian antibody may be a mouse antibody. The antibody, antibody region or extender fusion region may further comprise a linker. The linker may attach Mocha 1, VM24, beta-interferon, or a derivative or variant thereof to the extender peptide. A linker may attach the antibody region to the extender fusion region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The autoimmune disease may be a T cell mediated autoimmune disease. T cell mediated autoimmune diseases may include, but are not limited to, multiple sclerosis, type 1 diabetes, and psoriasis. In other cases, autoimmune disease lupus, Sjogren's syndrome, scleroderma, rheumatoid arthritis, dermatomyositis, Hashimoto's thyroiditis, Addison's disease, celiac disease, Crohn's disease, pernicious anemia, pemphigus vulgaris, vitiligo, autoimmune hemolytic anemia, idiopathic thrombocytopenia Purpura, myasthenia gravis, Odd's thyroiditis, Graves' disease, Guillain-Barré syndrome, acute disseminated encephalomyelitis, myoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, Goodpasture syndrome, Reiter's syndrome, Takaya's arteritis, temporal arteritis, Wegener's granulomatosis, generalized alopecia, Behcet's disease, chronic fatigue, ataxia, endometriosis, interstitial cystitis, neuromuscular dystonia, scleroderma, and vulvar pain. Lupus is acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, chronic cutaneous lupus erythematosus, discoid lupus erythematosus, childhood discoid lupus erythematosus, systemic discoid lupus erythematosus, topical discoid lupus erythematosus, frostbite lupus erythematosus (Hutchinson), erythema Lupus-lichen planus overlap syndrome, lupus steatohepatitis erythematosus (lupus erythematosus), lupus erythematosus, lupus erythematosus (lupus erythematosus) hypertrophic lupus erythematosus (lupus erythematosus), complement deficiency syndrome, weak lupus erythematosus, neonatal lupus erythematosus, and systemic lupus erythematosus including but not limited to. The disease or condition may be multiple sclerosis. The disease or condition may be diabetes.

Also provided herein is a method of preventing or treating a disease or condition in which modulation of a voltage-gated calcium channel is beneficial in a subject in need thereof, wherein one or more immunoglobulin fusion proteins disclosed herein Disclosed is a method comprising administering to a subject a composition comprising An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The voltage-gated calcium pathway may be a KCNA3 or K _v 1.3 pathway. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be Mocha 1 or a derivative or variant thereof. The therapeutic agent may be VM24 or a derivative or variant thereof. An immunoglobulin fusion protein or antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain may be derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a mouse antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach Mocha 1, VM24, or a derivative or variant thereof to the extender peptide. A linker may attach the antibody region to the extender fusion region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The disease or condition may be an autoimmune disease. The autoimmune disease may be a T cell mediated autoimmune disease. The disease or condition may be paroxysmal ataxia, seizures, or neuromuscular dystonia. Modulation of the voltage-gated calcium pathway may include inhibiting or blocking the voltage-gated calcium pathway. Regulation of the voltage-gated calcium channel may include activating the voltage-gated calcium channel.

Provided herein is a method of preventing or treating a metabolic disease or condition in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein start An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be GLP-1, exendin-4, FGF21 or a derivative or variant thereof. GLP-1 may be human GLP-1. The FGF21 may be human FGF21. An antibody or antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain may be derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a mouse antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach GLP-1, exendin-4, FGF21, or a derivative or variant thereof to the extender peptide. A linker may attach the antibody region to the extender fusion region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. Metabolic diseases and/or conditions include disorders of carbohydrate metabolism, disorders of amino acid metabolism, disorders of organic acid metabolism (organic aciduria), disorders of fatty acid oxidation and mitochondrial metabolism, disorders of porphyrin metabolism, disorders of purine or pyrimidine metabolism, disorders of steroid metabolism, mitochondrial dysfunction, peroxisomal dysfunction, urea cycle disorder, urea cycle defect or lysosomal storage disease. The metabolic disease or condition may be diabetes. In other instances, the metabolic disease or condition is glycogen storage disease, phenylketonuria, maple diabetes, glutaricemia type 1, carbamoyl phosphate synthetase I deficiency, alkaptonuria, medium chain acyl CoA dehydrogenase deficiency (MCADD: Medium) -chain acyl-coenzyme A dehydrogenase deficiency), acute intermittent porphyria, Lesch-Niehan syndrome, congenital lipid adrenal hyperplasia, congenital adrenal hyperplasia, Kerns-Ser syndrome, Zellweger syndrome, Gaucher disease, or Niemann-Pick disease have.

A method of preventing or treating a central nervous system (CNS) disorder in a subject in need thereof, comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. method is disclosed. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be GLP-1, exendin-4 or a derivative or variant thereof. GLP-1 may be human GLP-1. An antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain may be derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a mouse antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach GLP-1, exendin-4, or a derivative or variant thereof to the immunoglobulin domain or fragment thereof. A linker may attach the antibody region to the extender fusion region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The CNS disorder may be Alzheimer's disease (AD). Still other CNS disorders include, but are not limited to, encephalitis, meningitis, tropical spastic paraplegia, arachnoid cyst, Huntington's disease, Lockt-In's syndrome, Parkinson's disease, Tourette's, and multiple sclerosis.

A method of preventing or treating a disease or condition in a subject in need thereof wherein a GLP-1R and/or glucagon receptor (GCGR) agonist is beneficial, comprising one or more immunoglobulin fusion proteins disclosed herein Provided is a method comprising administering a composition to a subject. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be GLP-1, exendin-4 or a derivative or variant thereof. GLP-1 may be human GLP-1. An immunoglobulin fusion protein or antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain may be derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a mouse antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach GLP-1, exendin-4, or a derivative or variant thereof to the extender peptide. In other cases, the linker attaches the extender fusion region to the antibody region. The disease or condition may be a metabolic disease or disorder. The disease or condition may be diabetes. In other instances, the disease or condition may be obesity. Other diseases and/or conditions in which GLP-1R and/or GCGR agonists would benefit include, but are not limited to, dyslipidemia, cardiovascular disorders, and fatty liver disease.

Provided herein are methods of preventing or treating a blood disorder in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. . An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be erythropoietin, GMCSF or a derivative or variant thereof. The erythropoietin may be human erythropoietin. The GMCSF may be human GMCSF. An antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain may be derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a mouse antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach erythropoietin, GMCSF, or a derivative or variant thereof to the extender peptide. A linker may attach the antibody region to the extender fusion region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The blood disorder may be anemia. Examples of anemia include hereditary xerocytosis, congenital erythropoietic anemia, Rh incompatibility, infectious mononucleosis-associated anemia, drug-associated anemia, aplastic anemia, microcytic anemia, macrocytic anemia, static anemia, Hemolytic anemia, modified erythrocyte anemia, spherocyte anemia, sickle cell anemia, monochromatic anemia, hyperchromic anemia, hypochromic anemia, macroerythrocyte-chromatic anemia, microerythrocytic-hypochromatic anemia, static blood cell -chromic anemia, iron deficiency anemia, pernicious anemia, folate deficiency anemia, thalassemia, iron erythroblastic anemia, post-acute hemorrhagic anemia, sickle cell anemia, chronic anemia, achrestic anemia, autoimmune hemolytic anemia, Cooley anemia, weak immune hemolytic anemia, erythroblastic anemia, hypoplastic anemia, Diamond-Blackpan anemia, Pearson's anemia, transient anemia, Fanconi anemia, Lederer anemia, myelopathy, trophic anemia, prickly erythrocyte anemia, von Jaxie ( Von Jaksh) anemia, iron erythroblastic anemia, iron deficiency anemia, alpha thalassemia, beta thalassemia, hemoglobin h disease, acute acquired hemolytic anemia, warm autoimmune hemolytic anemia, cold autoimmune hemolytic anemia, primary cold autoimmune Hemolytic Anemia, Secondary Cold Autoimmune Hemolytic Anemia, Secondary Autoimmune Hemolytic Anemia, Primary Autoimmune Hemolytic Anemia, x-linked Ironhemoblastic Anemia, Pyridoxine Reactive Anemia, Nutritional Ironoblastic Anemia, Pyridoxine Deficiency-Induced Ironhemoblastic Anemia, copper-deficiency-induced ironoblastic anemia, cycloserine-induced ironoblastic anemia, chloramphenicol-induced ironoblastic anemia, ethanol-induced ironoblastic anemia, Weak-induced iron-erythroblastic anemia, toxin-induced iron-erythroblastic anemia, microerythrocyte hyperchromic anemia, macroerythrocyte hyperchromic anemia, megaloblastic-chromatic anemia, weak-induced immune hemolytic anemia, non-hereditary spheroblastic anemia , hereditary spheroblastic anemia, and congenital spheroblastic anemia. In other instances, the blood disorder may be malaria. Alternatively, the blood disorder may be lymphoma, leukemia, multiple myeloma, or myelodysplastic syndrome. The blood disorder may be neutropenia, Schwachmann-Diamond syndrome, Kostman syndrome, chronic granulomatosis, leukocyte adhesion deficiency, myeloperoxidase deficiency, or Chediak Higashi syndrome.

As a method of preventing or treating a disease or disorder in a subject in need thereof wherein stimulation or increase in white blood cell production is beneficial herein, a composition comprising one or more immunoglobulin fusion proteins disclosed herein is administered to the subject It provides a method comprising the step of: An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be GMCSF or a derivative or variant thereof. The GMCSF may be human GMCSF. An immunoglobulin fusion protein or antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain may be derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a mouse antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. A linker may attach the antibody region to the extender fusion region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The disease or disorder may be neutropenia, Schwachmann-Diamond syndrome, Kostman syndrome, chronic granulomatosis, leukocyte adhesion deficiency, myeloperoxidase deficiency, or Chediak-Higashi syndrome.

A method of preventing or treating a disease or disorder in a subject in need thereof for which stimulation or increase of red blood cell production is beneficial herein, comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein It provides a method comprising the step of: An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be erythropoietin or a derivative or variant thereof. The erythropoietin may be human erythropoietin. An antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain may be derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a mouse antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach erythropoietin, or a derivative or variant thereof, to the extender peptide. A linker may attach the antibody region to the extender fusion region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The disease or disorder may be anemia.

Provided herein are methods of preventing or treating obesity in a subject in need thereof, comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be GLP-1 or a derivative or variant thereof. GLP-1 may be human GLP-1. The therapeutic agent may be FGF21 or a derivative or variant thereof. The FGF21 may be human FGF21. The therapeutic agent may be exendin-4 or a derivative or variant thereof. An antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain may be derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a mouse antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach GLP-1, exendin-4, FGF21, or a derivative or variant thereof to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent.

Provided herein are methods of preventing or treating pain in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The subject may be a mammal. In some instances, the mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be Mamba 1 or a derivative or variant thereof. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach Mamba 1 or a derivative or variant thereof to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent.

A method of preventing or treating a disease or condition in a subject in need thereof wherein modulation of the sodium channel is beneficial, comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein; provides a method comprising An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The subject may be a mammal. In some instances, the mammal may be a human. Alternatively, the mammal may be a bovine. The one or more antibodies, antibody fragments, or immunoglobulin constructs further comprise a linker. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent.

A method of preventing or treating a disease or condition in a subject in need thereof in which modulation of an acid sensing ion channel (ASIC) is beneficial, comprising: one or more immunoglobulin fusion proteins disclosed herein; Provided is a method comprising administering to a subject a composition comprising An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The subject may be a mammal. In some instances, the mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be Mamba 1 or a derivative or variant thereof. The therapeutic agent may be a neutrophil elastase inhibitor or a derivative or variant thereof. The one or more antibodies, antibody fragments, or immunoglobulin constructs further comprise a linker. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. Modulation of ASIC may include inhibiting or blocking ASIC. Modulation of the ASIC may include activating the ASIC. The disease or condition may be a central nervous system disorder. In other instances, the disease or condition is pain.

Provided herein are methods of preventing or treating a pathogenic infection in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein . An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be alpha-interferon or a derivative or variant thereof. The therapeutic agent may be beta-interferon or a derivative or variant thereof. An antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain may be derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a mouse antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach alpha-interferon, beta-interferon, or a derivative or variant thereof to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The pathogenic infection may be a bacterial infection. The pathogenic infection may be a fungal infection. The pathogenic infection may be a parasitic infection. The pathogenic infection may be a viral infection. The viral infection may be a herpes virus.

Provided herein are methods of preventing or treating cancer in a subject in need thereof, comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be beta-interferon or a derivative or variant thereof. An antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. The immunoglobulin domain may be derived from a mammalian antibody. Alternatively, the immunoglobulin domain may be derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a mouse antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The cancer may be a hematologic malignancy. The hematologic malignancy may be leukemia or lymphoma. Hematological malignancies include B-cell lymphoma, T-cell lymphoma, follicular lymphoma, marginal zone lymphoma, hairy cell leukemia, chronic myelogenous leukemia, mantle cell lymphoma, nodular lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, or may be small lymphocytic leukemia.

Provided herein are methods of preventing or treating a disease or condition in a subject in need thereof, comprising administering to the subject a composition disclosed herein, wherein modulation of the receptor is beneficial. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises one or more immunoglobulin fusion proteins comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an amino acid sequence comprising an alpha helix and (i) an extender peptide comprising an amino acid sequence comprising no more than 7 amino acids based on or derived from an extra-long CDR3 or (ii) an amino acid sequence that does not comprise an extra-long CDR3; and (b) a therapeutic agent. The subject may be a mammal. In some instances, the mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be hGCSF or a derivative or variant thereof and the receptor may be GCSFR. The therapeutic agent may be erythropoietin or a derivative or variant thereof and the receptor may be an EPOR. The therapeutic agent may be exendin-4 or a derivative or variant thereof and the receptor may be GLP1R. The therapeutic agent may be GLP-1 or a derivative or variant thereof and the receptor may be GLP1R. The therapeutic agent may be hleptin or a derivative or variant thereof and the receptor may be LepR. The therapeutic agent may be hGH or a derivative or variant thereof and the receptor may be GHR. The therapeutic agent may be interferon-alpha or a derivative or variant thereof and the receptor may be an IFNR. The therapeutic agent may be interferon-beta or a derivative or variant thereof and the receptor may be an IFNR. The therapeutic agent may be relaxin or a derivative or variant thereof and the receptor may be LGR7. The therapeutic agent may be GMCSF or a derivative or variant thereof and the receptor may be GMCSFR. The one or more antibodies, antibody fragments, or immunoglobulin constructs further comprise a linker. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The disease or condition may be an autoimmune disease. The autoimmune disease may be a T cell mediated autoimmune disease. The disease or condition may be a metabolic disorder. The metabolic disorder may be diabetes. The disease or condition may be an inflammatory disorder. The inflammatory disorder may be multiple sclerosis. The disease or condition may be a cell proliferative disorder. The disease or condition may be a blood disorder. The blood disorder may be neutropenia. The blood disorder may be anemia. The disease or condition may be a pathogenic infection. The pathogenic infection may be a viral infection. The disease or condition may be a growth disorder. The disease or condition may be a cardiovascular condition. The cardiovascular condition may be acute heart failure. Modulation of a receptor may include inhibiting or blocking the receptor. Receptor modulation may include activating the receptor. The therapeutic agent may act as a receptor agonist. The therapeutic agent may act as a receptor antagonist.

Provided herein is a method for preventing or treating a disease in a mammal in need thereof, comprising administering to the mammal a pharmaceutical composition disclosed herein. In some embodiments, the disease may be an infectious disease. In certain embodiments, the infectious disease may be mastitis. In some embodiments, the infectious disease may be a respiratory disease. In certain embodiments, the respiratory disease may be a bovine respiratory disease of transport fever. In certain embodiments, the mammal in need may be a milking animal selected from the list comprising a cow, a camel, a donkey, a goat, a horse, a reindeer, a sheep, a water buffalo, a moose and a yak. In some embodiments, the mammal in need may be a bovine.

Provided herein is a method for preventing or treating mastitis in a milking animal, the method comprising providing to the milking animal an effective amount of a composition comprising one or more immunoglobulin fusion proteins disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. In some cases, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region is based on or derived from (a) an amino acid sequence comprising an alpha helix and (i) a very long CDR3 7 an extender peptide comprising an amino acid sequence comprising no more than five amino acids or (ii) an amino acid sequence that does not comprise a very long CDR3; and (b) a therapeutic agent. The therapeutic agent may be GCSF. The GCSF may be bovine GCSF. The GCSF may be human GCSF. In some embodiments, the milking animal may be a cow or a water buffalo.

Provided is a method of treating, inhibiting, and preventing a disease or condition in a subject in need thereof, by administering to the subject an effective amount of an immunoglobulin fusion protein or pharmaceutical composition disclosed herein. The immunoglobulin fusion protein can be substantially purified (eg, substantially free of substances limiting its effectiveness or causing undesirable side effects). The subject can be an animal, including but not limited to animals such as cows, pigs, sheep, goats, rabbits, horses, chickens, cats, dogs, mice, and the like. The subject may be a mammal. The subject may be a human. The subject may be a non-human primate. Alternatively, the subject may be a bovine. The subject may be an avian, reptile or amphibian.

additional uses

Also disclosed herein is the use of an immunoglobulin fusion protein (IFP) in the manufacture of a medicament for a disease or condition. The IFP may be any IFP disclosed herein. Disclosed herein is the use of an immunoglobulin fusion protein (IFP) comprising an antibody region attached to a non-antibody region in the manufacture of a medicament for the treatment of a disease or condition. Also disclosed herein is the use of an IFP comprising an antibody region attached to an extender fusion region in the manufacture of a medicament for the treatment of a disease or condition, wherein the extender fusion region comprises a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated at a location within the antibody region. The non-antibody region may be inserted within the antibody region. The non-antibody region may be inserted within an immunoglobulin heavy chain of the antibody region. The non-antibody region may be inserted within the immunoglobulin light chain of the antibody region. The non-antibody region may be conjugated to the antibody region. The non-antibody may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may comprise GCSF. The GCSF may be human GCSF. The therapeutic agent may be Mocha 1. The therapeutic agent may be VM24. The therapeutic agent may be exendin-4. The therapeutic agent may be erythropoietin The erythropoietin may be human erythropoietin. The therapeutic agent may be hleptin. The therapeutic agent may be growth hormone (GH). The growth hormone may be human growth hormone (hGH). The therapeutic agent may be interferon-alpha. The therapeutic agent may be interferon-beta. The therapeutic agent may be GLP-1. The therapeutic agent may be a neutrophil elastase inhibitor. The therapeutic agent may be relaxin. The therapeutic agent may be Mamba 1. The therapeutic agent may be elafin. The therapeutic agent may be betatropine. The therapeutic agent may be GDF11. The therapeutic agent may be GMCSF. The disease or condition may be an autoimmune disease, a heteroimmune disease or condition, an inflammatory disease, a pathogenic infection, a thromboembolic disorder, a respiratory disease or condition, a metabolic disease, a central nervous system (CNS) disorder, a bone disease or cancer. In other instances, the disease or condition is a blood disorder. In some instances, the disease or condition is obesity, diabetes, osteoporosis, anemia, or pain. The disease or condition may be a growth disorder.

Also disclosed herein is the use of an immunoglobulin fusion protein (IFP) in the manufacture of a medicament for the treatment of a cell proliferative disorder. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or less amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The cell proliferative disorder may be cancer. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. The non-antibody region may be inserted within the antibody region. The non-antibody region may be inserted within an immunoglobulin heavy chain of the antibody region. The non-antibody region may be inserted within the immunoglobulin light chain of the antibody region. The non-antibody region may be conjugated to the antibody region. The non-antibody region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule.

Also disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a metabolic disorder. The metabolic disorder may be diabetes. The diabetes may be type 1 diabetes. The diabetes may be type 2 diabetes. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be exendin-4. The therapeutic agent may be GLP-1. The therapeutic agent may be hleptin. The therapeutic agent may be betatropine.

Also disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of an autoimmune disease or condition. The IFP may be any IFP disclosed herein. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be Mocha 1. The therapeutic agent may be VM24.

Also disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of an inflammatory disease or condition. The inflammatory disease or condition may be multiple sclerosis. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be elaphine. The therapeutic agent may be interferon-beta.

Also disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a central nervous system disease or condition. The IFP may be any IFP disclosed herein. The central nervous system disease or condition may be pain. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be Mamba 1.

Also disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a cardiovascular disease or condition. The IFP may be any IFP disclosed herein. The cardiovascular disease or condition may be acute heart failure. The cardiovascular disease or condition may be cardiac hypertrophy. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be relaxin. The therapeutic agent may be GDF11.

Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a hematologic disease or condition. The IFP may be any IFP disclosed herein. The hematological disease or condition may be anemia. The hematologic disease or condition may be neutropenia. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be GCSF. The GCSF may be human GCSF. The therapeutic agent may be erythropoietin. The erythropoietin may be human erythropoietin. The treatment may be GMCSF.

Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a pathogenic infection. The IFP may be any IFP disclosed herein. The pathogenic infection may be a viral infection. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be interferon-alpha.

Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a growth disorder. The IFP may be any IFP disclosed herein. Examples of growth disorders include achondroplasia, juvenile achondroplasia, acromegaly, fatty genital dystrophy, dwarfism, megalomania, Brook Greenberg, hemitrophy, hypochondrosis, Janssen metachondrosis, Gowaski syndrome, Larry-Weil chondroostosis. , ischemia, lipomastosis, majeschi polydactyly syndrome, parietal osteogenic abnormal primary dwarfism type II, dwarfism, hyperproliferative syndrome, parastremmatic dwarfism, primary dwarfism, pseudochondral aplasia, psychosocial short stature, Sickle syndrome, short rib-polydactyly syndrome. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be growth hormone. The growth hormone may be human growth hormone (hGH).

Also disclosed herein is the use of an immunoglobulin fusion protein for the treatment of a disease or condition. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may comprise GCSF. The GCSF may be human GCSF. The therapeutic agent may be Mocha 1. The therapeutic agent may be VM24. The therapeutic agent may be exendin-4. The therapeutic agent may be erythropoietin. The erythropoietin may be human erythropoietin. The therapeutic agent may be hleptin. The therapeutic agent may be growth hormone (GH). The growth hormone may be human growth hormone (hGH). The therapeutic agent may be interferon-alpha. The therapeutic agent may be interferon-beta. The therapeutic agent may be GLP-1. The therapeutic agent may be relaxin. The therapeutic agent may be a neutrophil elastase inhibitor. The therapeutic agent may be Mamba 1. The therapeutic agent may be elafin. The therapeutic agent may be betatropine. The therapeutic agent may be GDF11. The therapeutic agent may be GMCSF. The disease or condition may be an autoimmune disease, a heteroimmune disease or condition, an inflammatory disease, a pathogenic infection, a thromboembolic disorder, a respiratory disease or condition, a metabolic disease, a central nervous system (CNS) disorder, a bone disease or cancer. In other instances, the disease or condition is a blood disorder. In some instances, the disease or condition is obesity, diabetes, osteoporosis, anemia, or pain. The disease or condition may be a growth disorder.

Disclosed herein is the use of an immunoglobulin fusion protein for treating a cell proliferative disorder in a subject in need thereof. The IFP may be any IFP disclosed herein. The cell proliferative disorder may be cancer. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule.

Disclosed herein is the use of an immunoglobulin fusion protein for treating a metabolic disorder in a subject in need thereof. The IFP may be any IFP disclosed herein. The metabolic disorder may be diabetes. The diabetes may be type 1 diabetes. The diabetes may be type 2 diabetes. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be exendin-4. The therapeutic agent may be GLP-1. The therapeutic agent may be hleptin. The therapeutic agent may be betatropine.

Disclosed herein is the use of an immunoglobulin fusion protein for treating an autoimmune disease or condition in a subject in need thereof. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be Mocha 1. The therapeutic agent may be VM24.

Disclosed herein is the use of an immunoglobulin fusion protein for treating an inflammatory disease or condition in a subject in need thereof. The IFP may be any IFP disclosed herein. The inflammatory disease or condition may be multiple sclerosis. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be elaphine. The therapeutic agent may be interferon-beta.

Disclosed herein is the use of an immunoglobulin fusion protein for treating a central nervous system disease or condition in a subject in need thereof. The IFP may be any IFP disclosed herein. The central nervous system disease or condition may be pain. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be Mamba 1.

Disclosed herein is the use of an immunoglobulin fusion protein for treating a cardiovascular disease or condition in a subject in need thereof. The IFP may be any IFP disclosed herein. The cardiovascular disease or condition may be acute heart failure. The cardiovascular disease or condition may be cardiac hypertrophy. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be relaxin. The therapeutic agent may be GDF11.

Disclosed herein is the use of an immunoglobulin fusion protein for treating a hematologic disease or condition in a subject in need thereof. The IFP may be any IFP disclosed herein. The hematological disease or condition may be anemia. The hematologic disease or condition may be neutropenia. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be GCSF. The GCSF may be human GCSF. The therapeutic agent may be erythropoietin. The erythropoietin may be human erythropoietin. The therapeutic agent may be GMCSF.

Disclosed herein is the use of an immunoglobulin fusion protein for treating a pathogenic infection in a subject in need thereof. The IFP may be any IFP disclosed herein. The pathogenic infection may be a viral infection. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be interferon-alpha.

Disclosed herein is the use of an immunoglobulin fusion protein for treating a growth disorder in a subject in need thereof. Examples of growth disorders include achondroplasia, juvenile achondroplasia, acromegaly, fatty genital dystrophy, dwarfism, gigantism, Brook Greenberg, hemitrophy, hypochondrosis, Janson metachondrosis, Kowski syndrome, Larry-Weil chondrodysplasia. , ischemia, lipomastosis, Mazeski polydactyly syndrome, parietal osteogenic dysplasia primary dwarfism type II, dwarfism, hyperplasia syndrome, parastrematic dwarfism, primary dwarfism, pseudocartilage aplasia, psychosocial short stature, Sickle syndrome, short rib- polydactyly syndrome and Silver-Russell syndrome. The IFP may be any IFP disclosed herein. An immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. The non-antibody region may comprise an extender peptide. The non-antibody region may comprise a linker peptide. The non-antibody region may comprise a proteolytic cleavage site. The immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region. The extender fusion region may comprise a therapeutic agent. The extender fusion region may comprise an extender peptide. The extender fusion region may comprise a linker peptide. The extender fusion region may comprise a proteolytic cleavage site. The IFP may comprise a non-antibody region attached to an antibody region, said antibody region comprising no more than 6 amino acids of a very long CDR3. The non-antibody region may comprise one or more therapeutic agents. In some cases, the immunoglobulin fusion protein may comprise an antibody region attached to an extender fusion region, the extender fusion region comprising: (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within the immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within the immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a location within the antibody region. An antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, or immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or a fragment thereof. In some instances, the immunoglobulin domain is derived from a mammalian antibody. Alternatively, the immunoglobulin domain is derived from a chimeric antibody. The immunoglobulin domain may be derived from an engineered antibody or a recombinant antibody. The immunoglobulin domain may be derived from a humanized antibody, a human engineered antibody, or a fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a mouse antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach the therapeutic agent to the extender peptide. A linker may attach the extender fusion region to the antibody region. The linker may attach the proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or a derivative or variant thereof. Alternatively, the therapeutic agent is a small molecule. The therapeutic agent may be growth hormone. The growth hormone may be human growth hormone (hGH).

pharmacological properties

Also disclosed herein are methods of improving one or more pharmacological properties of a therapeutic agent. The methods may include producing an immunoglobulin fusion protein disclosed herein. Examples of pharmacological properties may include, but are not limited to, half-life, stability, solubility, immunogenicity, toxicity, bioavailability, absorption, liberation, distribution, metabolization, and secretion. The glass may represent the release process of the therapeutic agent from the pharmaceutical formulation. Absorption may refer to the process by which a substance enters the blood circulation. Dispensing may refer to the dispersion or propagation of a substance through body fluids and tissues. Metabolism (or bioinformation, or inactivation) may refer to recognition by an organism in which a foreign substance is present and irreversible conversion of a parent compound to a daughter metabolite. Secretion may indicate the removal of a substance from the body.

The half-life of the therapeutic agent may be greater than the half-life of the unconjugated therapeutic agent. The half-life of the therapeutic agent is 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days after administration to the subject. It may be greater than 1, 11, 12, 13, or 14 days. The half-life of the therapeutic agent may be greater than 4 hours after administration to a subject. The half-life of the therapeutic agent may be greater than 6 hours after administration to a subject.

The half-life of the therapeutic agent may be increased by at least about 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 hours or more. The half-life of the therapeutic agent may be increased by at least about 2 hours. The half-life of the therapeutic agent may be increased by at least about 4 hours. The half-life of the therapeutic agent may be increased by at least about 6 hours. The half-life of the therapeutic agent may be increased by at least about 8 hours.

The half-life of the therapeutic agent is at least about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 times the half-life of the unconjugated therapeutic peptide. can be bigger The half-life of a therapeutic antibody described herein may be at least about 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 fold greater than the half-life of the unconjugated therapeutic peptide. The half-life of a therapeutic antibody described herein may be at least about 2-fold greater than the half-life of an unconjugated therapeutic peptide. The half-life of a therapeutic antibody described herein may be at least about 5-fold greater than the half-life of the unconjugated therapeutic peptide. The half-life of a therapeutic antibody described herein may be at least about 10-fold greater than the half-life of the unconjugated therapeutic peptide.

The half-life of the therapeutic antibody described herein is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 55%, 60%, greater than the half-life of the unconjugated therapeutic peptide; 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% greater. The half-life of a therapeutic antibody described herein may be at least about 10% greater than the half-life of the unconjugated therapeutic peptide. The half-life of a therapeutic antibody described herein may be at least about 20% greater than the half-life of the unconjugated therapeutic peptide. The half-life of a therapeutic antibody described herein may be at least about 30% greater than the half-life of the unconjugated therapeutic peptide. The half-life of a therapeutic antibody described herein may be at least about 40% greater than the half-life of the unconjugated therapeutic peptide. The half-life of a therapeutic antibody described herein may be at least about 50% greater than the half-life of the unconjugated therapeutic peptide.

Example

Example 1: Trastuzumab-coil- for expression in mammalian cells bGCSF Construction of fusion protein vectors

The gene encoding bovine GCSF (bGCSF) (SEQ ID NO: 186) was synthesized by Genescript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the immunoglobulin fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the bGCSF fragment. Sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), forming antiparallel coiled coils, were then added to the ends of the N- and C-terminal ends of the bGCSF-linker fragment. Subsequently, the PCR fragment encoding the bGCSF gene having an extender peptide and a linker was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to generate the Trp99-Met107 loop. replaced. Trastuzumab-coil-based bGCSF fusion protein was further modified to replace the hIgG1 CH1-CH3 constant region of Trastuzumab with the hIgG4 CH1-CH3 constant region comprising three mutations (S228P, F234A and L235A) to trastuzumab. Zumab-coil bGCSF HC (SEQ ID NO: 38) was generated. The amplified fusion gene was ligated in-frame to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of the trastuzumab-coil-based fusion protein. Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 2: bovine-coil- for expression in mammalian cells bGCSF Construction of fusion protein vectors

The gene encoding bovine GCSF (bGCSF) (SEQ ID NO: 186) was synthesized by Genescript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the immunoglobulin fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the bGCSF fragment. Sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), forming antiparallel coiled coils, were then added to the ends of the N- and C-terminal ends of the bGCSF-linker fragment. Subsequently, a PCR fragment encoding the bGCSF gene having an extender peptide and a linker was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of a bovine IgG antibody (BLV1H12) using overlap extension PCR, and bovine-coil bGCSF HC (SEQ ID NO: 39) was created. The amplified fusion gene was ligated in-frame to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of a bovine-coil-based fusion protein. Similarly, the gene encoding the light chain of a bovine IgG antibody (SEQ ID NO: 18) was cloned into the pFuse framework vector. The obtained expression vector was confirmed by DNA sequencing.

Example 3: Trastuzumab-coil- bGCSF and small-coil- bGCSF Expression and purification of based fusion proteins

Trastuzumab-coil-bGCSF fusion protein Trastuzumab-coil-bGCSF based fusion protein by transient transfection of free HEK293 cells with vectors encoding heavy chain (SEQ ID NO: 38) and trastuzumab light chain (SEQ ID NO: 1) was expressed. Free-form HEK293 cells were transiently transfected with vectors encoding bovine-coil-bGCSF fusion protein heavy chain (SEQ ID NO: 39) and bovine light chain (SEQ ID NO: 18) to express bovine-coil-bGCSF based fusion protein. The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. Fusion proteins were purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel. As shown in Fig. 4, lane 1 depicts the protein ladder, lane 2 depicts bovine-coil IgG, lane 3 depicts DTT treated bovine-coil IgG, and lane 4 depicts bovine-coil- Depicts bGCSF IgG, lane 5 depicts DTT treated bovine-coil-bGCSF IgG, lane 6 depicts trastuzumab-coil-bGCSF IgG, and lane 7 depicts DTT treated trastuzumab-coil-bGCSF. IgG is shown, lane 8 shows Trastuzumab IgG and lane 9 shows Trastuzumab IgG treated with DTT.

Example 4: Trastuzumab-coil on mouse NFS-60 cells bGCSF Fusion proteins and bovine-coils bGCSF In vitro study of fusion protein proliferative activity

Mouse NFS-60 cells were obtained from the American Type Culture Collection (ATCC) (VA) and stimulated with 10% fetal bovine serum (FBS), 0.05 mM 2-mercaptoethanol and 62 ng/ml human macrophage colonies. It was cultured in RPMI-1640 medium supplemented with factor (M-CSF). For proliferation assays, mouse NFS-60 cells were washed three times with RPMI-1640 medium and resuspended at a density of 1.5×10 ⁵ cells/ml in RPMI-1640 medium supplemented with 10% FBS and 0.05 mM 2-mercaptoethanol. did In a 96-well plate, 100 μl of cell suspension was added to each well, followed by Trastuzumab IgG (SEQ ID NOs: 22 and 19), Trastuzumab-coil-bGCSF IgG (SEQ ID NOs: 69 and 19), bovine-coil IgG (SEQ ID NOs: 36 and 271), bovine-coil-bGCSF IgG (SEQ ID NOs: 70 and 36), and bGCSF (SEQ ID NO: 227) were added at various concentrations. Plates were incubated for 72 hours at 37° C. in a 5% CO ₂ incubator. Cells were then treated with AlamarBlue (Invitrogen) (1/10 volume of cell suspension) for 4 hours at 37° C. For each well, fluorescence was read at 595 nm to indicate cell viability, Table 13. [Figure 6] graphically shows the data.Ec ₅₀ of trastuzumab-coil-bGCSF IgG is 2.49 + 0.26 ng/mL.EC ₅₀ of bovine-coil-bGCSF IgG is 2.55 + The EC ₅₀ of bGCSF was 4.87 + 0.29 ng/mL.

[Table 13]

Example 5: Her2 Trastuzumab-coil- to receptor bGCSF's Combination

The binding affinity of the trastuzumab-coil-bGCSF fusion protein to the Her2 receptor was investigated by ELISA. Human Her2-Fc chimera (5 ug/mL) (R&D Systems) was coated in 96-well ELISA plates overnight at 4°C and then blocked with 1% BSA in PBS (pH7.4) at 37°C for 2 h. After washing with 0.05% Tween-20 in PBS (pH7.4), trastuzumab IgG (SEQ ID NOs: 22 and 19) and trastuzumab-coil-bGCSF (SEQ ID NOs: 69 and 19) fusion proteins were each added at various concentrations. It was added to the wells and incubated for 2 hours at 37°C. Subsequently, a goat polyclonal anti-human kappa light chain antibody (Sigma) with HRP conjugate was added and incubated at 37° C. for 2 hours. Subsequently, the wells were washed, and a fluorogenic peroxidase substrate was added to each well, and binding affinity was investigated based on the fluorescence intensity at 425 nm. Table 2 shows the fluorescence intensity at 425 nm of trastuzumab IgG and trastuzumab-coil-bGCSF IgG. [Fig. 7] shows the data of Table 14 as a graph. As shown in FIG. 7 , line 1 represents trastuzumab IgG and line 2 represents trastuzumab-coil-bGCSF IgG. The EC ₅₀ of Trastuzumab IgG was 110 + 14 pM.

[Table 14]

Example 6: for expression in mammalian cells BLV1H12 betatropine Construction of based fusion protein vectors

The gene encoding betatropin (SEQ ID NO: 198) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the immunoglobulin fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the betatrophin fragment. Subsequently, the PCR fragment encoding the gene of interest was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of the bovine IgG antibody (BLV1H12) using overlap extension PCR to generate a BLV1H12-direct betatrophin fusion (SEQ ID NO: 118) did To generate the BLV1H12-coil betatrophin-based fusion protein, the sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), which form antiparallel coiled coils, were combined with that of the betatrophin linker fragment. added at the end of the N- and C-terminus. Subsequently, a PCR fragment containing betatrophin, a linker, and an extender peptide was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of BLV1H12 using overlap extension PCR to trastuzumab-coil betatrophin (CDRH3) HC (SEQ ID NO: 66). The amplified fusion gene was ligated in-frame to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of the BLV1H12-betatropin-based fusion protein. Similarly, the gene encoding the light chain of the BLV1H12 antibody (SEQ ID NO: 18) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 7: BLV1H12 betatropine Expression and purification of fusion proteins

Free HEK293 cells were transiently transfected with vectors encoding the BLV1H12-direct betatrophin fusion protein heavy chain (SEQ ID NO: 140) and BLV1H12 light chain (SEQ ID NO: 36) to express the BLV1H12-direct betatrophin fusion protein. BLV1H12-coil betatrophin fusion protein was expressed by transient transfection of free HEK293 cells with vectors encoding the BLV1H12-coil betatrophin fusion protein heavy chain (SEQ ID NO: 97) and BLV1H12 light chain (SEQ ID NO: 36). The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. The fusion protein was purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by Western blot ( FIG. 8 ). As shown in FIG. 8 , lane 1 includes a protein ladder, lane 2 includes DTT-treated BLV1H12-coil betatrophin fusion proteins (SEQ ID NOs: 97 and 36), and lane 3 includes BLV1H12-coil beta trophin fusion proteins (SEQ ID NOs: 97 and 36).

Example 8: Trastuzumab-direct for expression in mammalian cells bGCSF Construction of protein vectors

The gene encoding bGCSF (SEQ ID NO: 186) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the immunoglobulin fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the bGCSF fragment. Subsequently, the PCR fragment encoding the gene of interest is grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to generate a trastuzumab-direct bGCSF fusion (SEQ ID NO: 101) . The amplified fusion gene was ligated in-frame to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of a trastuzumab-bGCSF based fusion protein. Similarly, the gene encoding the light chain of the trastuzumab antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 9: Trastuzumab-direct bGCSF Expression and purification of fusion proteins

Free HEK293 cells were transiently transfected with vectors encoding the trastuzumab-direct bGCSF fusion protein heavy chain (SEQ ID NO: 123) and trastuzumab light chain (SEQ ID NO: 19) to express the trastuzumab-direct bGCSF fusion protein . The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. The fusion protein was purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel ( FIG. 10 ). As shown in [Fig. 10], lane 1 contains a protein ladder, lane 2 contains trastuzumab-direct bGCSF fusion proteins (SEQ ID NOs: 123 and 19), and lane 3 contains DTT-treated trastuzumab- direct bGCSF fusion proteins (SEQ ID NOs: 123 and 19).

Example 10: Trastuzumab-direct to mouse NFS-60 cells bGCSF In vitro study of fusion protein proliferative activity

Mouse NFS-60 cells were obtained from the American Type Culture Collection (ATCC) (VA), washed three times with RPMI-1640 medium, and RPMI- supplemented with 10% fetal bovine serum (FBS) and 0.05 mM 2-mercaptoethanol. It was resuspended in 1640 medium at a density of 1.5×10 ⁵ cells/ml. In a 96 well plate, 100 μl of cell suspension was added to each well followed by addition of trastuzumab-direct bGCSF IgG (SEQ ID NOs: 123 and 19) and bGCSF (SEQ ID NO: 227) at various concentrations. Plates were incubated for 72 hours at 37° C. in a 5% CO ₂ incubator. The cells were then treated with Alamar Blue (Invitrogen) (1/10 volume of the cell suspension) at 37° C. for 4 hours. Cell viability was indicated by reading fluorescence at 595 nm for each well. [Fig. 11] is a graph showing data. The EC ₅₀ of trastuzumab-direct-bGCSF IgG was 1.8 + 0.4 ng/mL. The EC ₅₀ of bGCSF was 1.3 + 0.2 ng/mL.

Example 11: Trastuzumab-coil- for expression in mammalian cells exendin -4 Construction of fusion protein vectors

The gene encoding exendin-4 (Ex-4) (SEQ ID NO: 188) was synthesized by Genescript or IDT, and synthesized by polymerase chain reaction (PCR). The cleavage site of factor Xa (SEQ ID NO: 182) was placed before the N-terminus of Ex-4. To increase the folding and stability of the fusion protein, a flexible CGGGGS linker (SEQ ID NO: 276) was added just before the Factor Xa protease cleavage site and a GGGGSC linker (SEQ ID NO: 277) was added to the C-terminal end of the Ex-4 gene fragment. Then, sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), forming antiparallel coiled coils, were added to the ends of the N- and C-terminal ends of the exendin-4 linker fragment . Subsequently, the PCR fragment encoding the gene of interest was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to replace the Trp99-Met107 loop. Trastuzumab-coil-exendin-4 based fusion protein was modified to have a human hIgG1 CH1-CH3 constant region comprising 7 mutations (E233P, L234V, L235A, AG236, A327G, A330S, and P331S) to trastuzumab -Coil-Ex4 HC fusion (SEQ ID NO: 40) was generated. The amplified fusion gene was ligated in-frame to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of a trastuzumab-coil-exendin-4 based fusion protein. Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 12: trastuzumab-coil- exendin Expression and purification of -4-based fusion proteins

Free HEK293 cells were transiently transfected with vectors encoding trastuzumab-coil-exendin-4 fusion protein heavy chain (SEQ ID NO: 71) and trastuzumab light chain (SEQ ID NO: 19) to trastuzumab-coil-exendin Dean-4 based fusion proteins were expressed. The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. Fusion proteins were purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel. Trastuzumab-coil based Ex-4 fusion protein was further treated with factor Xa protease (GE Healthcare) according to the manufacturer's protocol to liberate the N-terminus of the fused peptide. After treatment, the fusion protein was purified again by Protein A/G affinity column to remove protease, and analyzed by SDS-PAGE gel as shown in [Fig. 12]. Lane 1 is a protein marker. Lane 2 is Trastuzumab-coil-Ex-4 IgG (SEQ ID NOs: 71 and 19). Lane 3 is DTT treated Trastuzumab-coil-Ex-4 IgG (SEQ ID NOs: 71 and 19). Lane 4 is a protein marker. Lane 5 is trastuzumab-coil-Ex-4 IgG (SEQ ID NOs: 71 and 19) after cleavage with factor Xa, which liberates the N-terminus of the Ex-4 peptide to release trastuzumab-coil-Ex-4 RN IgG generated, and RN is an abbreviation for the free N-terminus. Lane 6 is DTT treated trastuzumab-coil-Ex-4 RN IgG.

Example One 3: Trastuzumab-coil- exendin -4 IgG Electrospray Ionization Mass Spectrometry (ESI-MS)

10 μg of purified trastuzumab-coil-exendin-4 heavy chain (HC) fusion (SEQ ID NOs: 71 and 19) in PBS (pH 7.4) was mixed with 1 μl (500 units) of peptide-N-glucosidase (NEB) ) at 37° C. overnight, then 50 mM DTT was added. Fusion proteins were analyzed by ESI-MS using Agilent Technology's 6520 Q-TOF LC/MS. A chromatograph is shown in [FIG. 13]. The expected molecular weight of trastuzumab-coil-exendin-4 HC is 56,880 Da. The measured molecular weight of trastuzumab-coil-exendin-4 HC was 56,748 Da. The measured molecular weight is related to the expected molecular weight without the first amino acid glutamic acid (E).

Example One 4: Trastuzumab-coil- exendin -4 RN IgG Electrospray Ionization Mass Spectrometry (ESI-MS)

10 μg of purified, factor Xa cleaved trastuzumab-coil-exendin-4 heavy chain (HC) fusion (SEQ ID NOs: 71 and 19) in PBS pH 7.4 was mixed with 1 μl (500 units) of peptide-N- After overnight treatment with glucosidase (NEB) at 37° C., 50 mM DTT was added. The cleaved fusion protein fragment was analyzed by ESI-MS using Agilent Technology's 6520 Q-TOF LC/MS. The chromatograph of the N-terminal fragment is shown in Fig. 14(A) and the chromatograph of the C-terminal fragment is shown in Fig. 14(B). The expected molecular weight of the trastuzumab-coil-exendin-4 HC RN N-terminal fragment is 13,309 Da. The measured molecular weight of the trastuzumab-coil-exendin-4 HC RN N-terminal fragment was 13,307 Da. The expected molecular weight of the trastuzumab-coil-exendin-4 HC RN C-terminal fragment is 43,589 Da. The measured molecular weight of the trastuzumab-coil-exendin-4 HC RN C-terminal fragment was 43,458 Da.

Example 15: to the GLP-1 receptor (GLP-1R) for trastuzumab -coil exendin -4 In vitro study of fusion protein activation activity

HEK293 cells overexpressing surface GLP-1R and cAMP-responsive luciferase reporter genes were seeded in 384 well plates at a density of 5,000 cells per well. After incubation for 24 hours at 37° C. under 5% CO ₂ , cells were transfected with exendin-4 peptide (SEQ ID NO: 228), trastuzumab (SEQ ID NOs: 19 and 22), trastuzumab-coil exendin-4 (SEQ ID NO: 228) Nos. 71 and 19), and Trastuzumab-coil exendin-4 (SEQ ID NOs: 71 and 19) RNs were treated at various concentrations and incubated for an additional 24 hours. Subsequently, a luciferase assay was performed using One-Glo luciferase reagent according to the manufacturer's (Promega) instructions. [Fig. 15] is a graph showing data. The EC ₅₀ of exendin-4 was 0.03 + 0.004 nM. The EC ₅₀ of trastuzumab-coil exendin-4 was 3.8 + 0.2 nM. The EC ₅₀ of trastuzumab-coil exendin-4 RN was 0.01 + 0.001 nM.

Example 16: trastuzumab-coil- exendin -4 In vitro study of fusion protein glucagon receptor activation assay

HEK293 cells overexpressing glucagon receptor (GCGR) and CRE-Luc reporter were cultured in DMEM with 10% FBS at 37° C. under 5% CO ₂ . Cells were seeded in 384 well plates at a density of 5,000 cells per well and glucagon, exendin-4 peptide (SEQ ID NO: 228), trastuzumab (SEQ ID NO: 19 and 22), trastuzumab-coil exendin-4 (SEQ ID NO: SEQ ID NO: 71 and 19), and trastuzumab-coil exendin-4 (SEQ ID NOs: 71 and 19) RN fusion proteins were treated at various concentrations under 5% CO ₂ at 37° C. for 24 hours. Thereafter, the luminescence intensity was measured according to the manufacturer's instructions using on-glo (Promega, WI) luciferase reagent. [Fig. 16] is a graph showing data.

Example 17: Drug of trastuzumab-coil-Ex-4 RN fusion protein in mice dynamics

Ex-4 (SEQ ID NO: 228) (1.6 mg/kg) and trastuzumab-coil-Ex-4 (SEQ ID NOs: 71 and 19) RN fusion proteins (2.8 mg/kg) were administered intravenously to CD1 mice (N=3). Administered by intravenous (iv) or subcutaneous (sc) injection. Blood samples were collected on days 0-8 for Ex-4 peptide and days 0-14 for trastuzumab-coil-Ex-4 RN fusion protein. Residual activity was analyzed using HEK 293-GLP-1R-CRE-Luc cells. Data were normalized by choosing the maximum concentration at the first time point (30 min) for intravenous injection. Data were normalized by selecting the maximum concentration at the second time point (day 1) for subcutaneous injections. The ratio to the maximum concentration was plotted against the time of blood sample collection, and the data were fitted with a first-order equation A=A0e-kt (where A0 is the initial concentration, t is the time, and k is the first-order rate constant). The half-life was determined. [Fig. 17] is a graph showing data. [Fig. 17(A)] shows intravenous injection. [Fig. 17(B)] shows the subcutaneous injection. t _{1/2 of} exendin-4(iv) was 1.5 + 0.2 hours. The t _{1/2 of} trastuzumab-coil exendin-4 RN(iv) was 2.4 + 0.1 days. The t _{1/2 of} trastuzumab-coil exendin-4 RN (sc) was 3.9 + 1.2 days.

Example 18: Drug of trastuzumab-coil-Ex-4 RN fusion protein in mice kinetics

A dose of Ex-4 (SEQ ID NO: 228) (20 μg/kg), trastuzumab (SEQ ID NOs: 19 and 22) (8 mg/kg), and various concentrations of trastuzumab-coil-Ex-4 RN ( SEQ ID NOs: 71 and 19) fusion proteins were administered to CD1 mice (N=5) by subcutaneous (sc) injection. Glucose (3 g/kg, po) was given at 30 minutes, 24, 48, 72, 96, 120, 144, 168, and 216 hours post-dose, immediately before glucose load and 15, 30, 45 after glucose load Blood glucose was measured at , 60, and 120 min. [Fig. 18] graphically shows data at 30 minutes, 24, 48, 72, 96, 120, 144, 168, and 216 hours after single dose treatment.

Example 19: Drug of trastuzumab-coil-Ex-4 fusion protein in mice kinetics

One dose of Ex-4 (SEQ ID NO: 228) (20 μg/kg), trastuzumab (SEQ ID NOs: 19 and 22) (8 mg/kg), and various concentrations of trastuzumab-coil-Ex-4 (SEQ ID NO: 19 and 22) Nos. 71 and 19) fusion proteins were administered to CD1 mice (N=5) by subcutaneous (sc) injection. After giving glucose (3 g/kg, po) at 2, 24, 48, 72, 96, 120, and 144 hours post-dose treatment, immediately before the glucose load, and 15, 30, 45, 60, and after the glucose load, and Blood glucose was measured at 120 minutes. [Fig. 19] graphically shows data at 2, 24, 48, 72, 144, 168, and 216 hours after single dose treatment.

Example 20: Her2 for the receptor Trastuzumab-coil- exendin -4 bond

The binding affinity of the trastuzumab-coil-exendin-4 fusion protein to the Her2 receptor is investigated by ELISA. Human Her2-Fc chimera (5 ug/mL) (R&D Systems) is coated in 96-well ELISA plates overnight at 4°C, followed by blocking with 1% BSA in PBS (pH 7.4) at 37°C for 2 h. After washing with 0.05% Tween-20 in PBS (pH7.4), trastuzumab IgG (SEQ ID NOs: 19 and 22) and trastuzumab-coil-exendin-4 (SEQ ID NOs: 71 and 19) fusion proteins were mixed with various concentration and incubate for 2 h at 37°C. Subsequently, a goat polyclonal anti-human kappa light chain antibody with HRP conjugate (Sigma) is added and incubated at 37° C. for 2 hours. Subsequently, the wells are washed and a fluorogenic peroxidase substrate is added to each well to examine the binding affinity based on the fluorescence intensity at 425 nm.

Example 21: HER2 Trastuzumab-coil- to receptor exendin -4 of bonding flow cell analyze

HER2-overexpressing SKBR3 cells are cultured in DMEM with 10% FBS and 1% penicillin and streptomycin. Cells were washed 3 times with cold PBS, blocked with 2% BSA in PBS, and treated with 10 or 100 nM of Trastuzumab (SEQ ID NOs: 19 and 22) and Trastuzumab-CDR fusion proteins (SEQ ID NOs: 71 and 19). Incubate with gentle mixing for 2 hours at 4°C. Unbound antibody is removed by washing with 2% BSA in PBS. Thereafter, the cells were stained with FITC anti-human IgG Fc (KPL, Inc., MD) with gentle mixing at 4° C. for 1 hour, washed with PBS, and analyzed by flow cytometry.

Example 22: Construction of Trastuzumab-Coil-Mocha Fusion Protein Vector for Expression in Mammalian Cells

The gene encoding Mocha (SEQ ID NO: 189) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the Mocha fragment. Sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), which form antiparallel coiled coils, were then added to the ends of the N- and C-terminal ends of the mocha-linker fragment. Subsequently, a PCR fragment encoding the mocha gene having an extender peptide and a linker was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to replace the Trp99-Met107 loop. Trastuzumab-coil-Mocha-based fusion protein was further modified to replace the hIgG1 CH1-CH3 constant region of Trastuzumab with the hIgG4 CH1-CH3 constant region comprising three mutations (S228P, F234A and L235A) Stuzumab-coil-Mocha IgG (SEQ ID NO: 41) was generated. The amplified fusion gene was ligated to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of the trastuzumab-coil-mocha-based fusion protein. Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 23: Expression and purification of trastuzumab-coil-mocha based fusion protein

Trastuzumab-coil-Mocha based fusion protein by transient transfection of free HEK293 cells with vectors encoding the trastuzumab-coil-mocha fusion protein heavy chain (SEQ ID NO: 72) and trastuzumab light chain (SEQ ID NO: 19) to express The expressed fusion protein is secreted into the culture medium and recovered 48 and 96 hours after transfection. The fusion protein was purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel as shown in FIG. 20 . Lane 1 represents protein molecular weight markers. Lane 2 shows purified trastuzumab-coil-mocha IgG. Lane 3 shows purified trastuzumab-coil-mocha IgG treated with DTT.

Example 24: Construction of Trastuzumab-Coil-VM24 Fusion Protein Vector for Expression in Mammalian Cells

The gene encoding VM24 (SEQ ID NO: 190) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the VM24 fragment. Then, sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), forming antiparallel coiled coils, were added to the ends of the N- and C-terminus of the VM24-linker fragment. Subsequently, the PCR fragment encoding the gene of interest was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to replace the Trp99-Met107 loop. Trastuzumab-coil-VM24 based fusion protein was further modified to replace the hIgG1 CH1-CH3 constant region of Trastuzumab with the hIgG4 CH1-CH3 constant region comprising three mutations (S228P, F234A and L235A) to SEQ ID NO: 42 was produced. The amplified fusion gene was ligated to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of a trastuzumab-coil-VM24 based fusion protein. Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 25: Expression and purification of trastuzumab-coil-VM24 based fusion protein

Trastuzumab-coil-VM24 fusion protein Trastuzumab-coil-VM24 based fusion protein by transient transfection of free HEK293 cells with vectors encoding heavy chain (SEQ ID NO: 73) and trastuzumab light chain (SEQ ID NO: 19) to express The expressed fusion protein is secreted into the culture medium and recovered 48 and 96 hours after transfection. The fusion protein was purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel as shown in FIG. 20 . Lane 1 represents protein molecular weight markers. Lane 4 shows purified trastuzumab-coil-Vm24 IgG. Lane 5 shows purified trastuzumab-coil-Vm24 IgG treated with DTT.

: human peripheral blood mononuclear cells ( PBMC )/trastuzumab-coil-mocha fusion protein and trastuzumab-coil- on T cell activation Vm24 In vitro study of fusion protein inhibitory activity

Human PBMCs were isolated from fresh venous blood from healthy donors by Ficoll gradient centrifugation, then resuspended in RPMI1640 medium containing 10% FBS and plated in 96-well plates at a density of 1×10 ⁶ cells/mL. Human T cells were isolated from the isolated PBMCs using a T cell enrichment kit. Purified PBMCs and T cells were mixed with various concentrations of purified trastuzumab-coil mocha (SEQ ID NOs: 72 and 19) and trastuzumab-coil Vm24 (SEQ ID NOs: 73 and 19) fusion proteins at 37° C. under 5% CO ₂ After preheating for 1 hour, they were activated by anti-CD3 and CD28 antibodies. After 24 hours of treatment, the supernatant was collected and the secreted TNF-α level was measured using an ELISA kit. Figure 21 graphically depicts in vitro inhibition of T cell activation data. The EC ₅₀ of trastuzumab-coil mocha IgG (SEQ ID NOs: 72 and 19) was 269 + 46 nM. The EC ₅₀ of Trastuzumab-coil Vm24 IgG (SEQ ID NOs: 73 and 19) was 178 + 104 nM.

Example 27: Trastuzumab-coil- for expression in mammalian cells hGCSF Construction of fusion protein vectors

The gene encoding human GCSF (hGCSF) (SEQ ID NO: 187) was synthesized by Genescript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the hGCSF fragment. Sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), forming antiparallel coiled coils, were then added to the ends of the N- and C-terminal ends of the bGCSF-linker fragment. To generate the CDRH3 fusion, a PCR fragment encoding the gene of interest was grafted into the complementarity determining region 3 (CDRH3) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to replace the Trp99-Met107 loop. To generate the CDRH2 fusion, a PCR fragment encoding the gene of interest was grafted into the complementarity determining region 2 (CDRH2) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to replace Thr54-Asn55. To generate a CDRL3 fusion, a PCR fragment encoding a gene of interest was grafted into the complementarity determining region 3 (CDRL3) of the light chain of the trastuzumab IgG antibody using overlap extension PCR to replace Thr93-Pro95. The trastuzumab-coil-hGCSF based fusion protein was modified to have a human hIgG1 CH1-CH3 constant region comprising 7 mutations (E233P, L234V, L235A, AG236, A327G, A330S, and P331S). The amplified fusion gene was ligated to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of the trastuzumab-coil-hGCSF-based fusion protein. Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 28: trastuzumab-coil- hGCSF Expression and purification of based fusion proteins

Trastuzumab-coil-hGCSF fusion protein (CDRH3) heavy chain (SEQ ID NO: 74) with trastuzumab light chain (SEQ ID NO: 9), trastuzumab-coil-hGCSF fusion protein (CDRH2) heavy chain with trastuzumab light chain, and trastuzumab Free-form HEK293 cells are transiently transfected with vectors encoding the stuzumab-coil-hGCSF fusion protein (CDRL3) light chain and trastuzumab heavy chain to express the trastuzumab-coil-hGCSF-based fusion protein. The expressed fusion protein is secreted into the culture medium and recovered 48 and 96 hours after transfection. Fusion proteins are purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel. 22 depicts purified trastuzumab-coil-hGCSF based fusion protein. Lane 1 shows purified trastuzumab-coil hGCSF (CDRH2) IgG. Lane 2 shows purified trastuzumab-coil hGCSF (CDRH2) IgG treated with DTT. Lane 3 represents protein molecular weight markers. Lane 4 shows purified trastuzumab-coil hGCSF (CDRL3) IgG. Lane 5 shows purified trastuzumab-coil hGCSF (CDRL3) IgG treated with DTT.

Example 29: trastuzumab-coil- hGCSF Electrospray Ionization Mass Spectrometry (ESI-MS) of Based Fusion Proteins

10 μg of purified trastuzumab-coil-hGCSF (CDRH2) in PBS (pH 7.4) was treated with 1 μl (500 units) of peptide-N-glucosidase (NEB) at 37° C. overnight, followed by 50 mM DTT was added. Fusion proteins were analyzed by ESI-MS using Agilent Technology's 6520 Q-TOF LC/MS. A chromatograph is shown in [FIG. 23(A)]. The expected molecular weight of trastuzumab-coil-hGCSF (CDRH2) HC is 71,472 Da. The measured molecular weight of trastuzumab-coil-hGCSF (CDRH2) HC was 72,300 Da. The measured molecular weight correlates with O-glycosylation of hGCSF. 10 μg of purified trastuzumab-coil-hGCS (CDRL3) in PBS (pH 7.4) was treated with 1 μl (500 units) of peptide-N-glucosidase (NEB) at 37° C. overnight, followed by 50 mM DTT was added. Fusion proteins were analyzed by ESI-MS using Agilent Technology's 6520 Q-TOF LC/MS. A chromatograph is shown in [Fig. 23(B)]. The predicted molecular weight of trastuzumab-coil-hGCSF (CDRL3) LC is 45,746 Da. The measured molecular weight of trastuzumab-coil-hGCSF (CDRL3) LC was 46,692 Da. The measured molecular weight correlates with O-glycosylation of hGCSF.

Example 30: HER2 Trastuzumab-coil for receptors hGCSF Binding of based fusion proteins

HER2-overexpressing SKBR3 cells were cultured in DMEM containing 10% FBS and 1% penicillin and streptomycin. Cells were washed 3 times with cold PBS, blocked with 2% BSA in PBS, and trastuzumab and trastuzumab-CDR fusion proteins, trastuzumab-coil-hGCSF (CDRH2) and trastuzumab at 10 or 100 nM. -Coil-hGCSF (CDRL3) was incubated with gentle mixing at 4°C for 2 hours. Unbound antibody was removed by washing with 2% BSA in PBS. Thereafter, the cells were stained with FITC anti-human IgG Fc (KPL, Inc., MD) with gentle mixing at 4° C. for 1 hour, washed with PBS, and analyzed by flow cytometry. 24 depicts a flow cytometry histogram.

Example 31: Trastuzumab-coil on mouse NFS-60 cells hGCSF In vitro study of fusion protein proliferative activity

Mouse NFS-60 cells were cultured in RPMI-1640 medium supplemented with 10% FBS, 0.05 mM 2-mercaptoethanol and 62 ng/ml human macrophage colony stimulating factor (M-CSF). To investigate the proliferative activity of trastuzumab-hGCSF fusion proteins, cells were washed three times with RPMI-1640 medium containing 10% FBS and RPMI-1640 medium supplemented with 10% FBS and 0.05 mM 2-mercaptoethanol. It was resuspended at a density of 1.5 × 10 ⁵ cells/ml in a 96-well plate ( 1.5×10 ⁴ cells per well) and incubated for 72 hours at 37° C. under 5% CO ₂ . Thereafter, the cells were treated with Alamar Blue (Invitrogen) at 37° C. for 4 hours. The fluorescence intensity measured at 595 nm is proportional to cell viability. [Fig. 25] is a graph showing data. The EC ₅₀ of hGCSF was 1.7 + 0.3 ng/mL. The EC ₅₀ of Trastuzumab-coil hGCSF (CDRH2) was 0.4 + 0.1 ng/mL. The EC ₅₀ of Trastuzumab-coil hGCSF (CDRL3) was 0.9 + 0.1 ng/mL.

Example 32: Trastuzumab-coil- for expression in mammalian cells hEPO Construction of fusion protein vectors

The gene encoding hEPO (SEQ ID NO: 192) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the immunoglobulin fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the hEPO fragment. Then, sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), forming antiparallel coiled coils, were added to the ends of the N- and C-terminal ends of the hEPO-linker fragment. Subsequently, a PCR fragment encoding the hEPO gene having an extender peptide and a linker was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to replace the Thr99-Met107 loop. Trastuzumab-coil hEPO (CDRH3) HC by replacing the CH1-CH3 constant region of the Trastuzumab-coil hEPO (CDRH3) heavy chain with a human IgG4 CH1-CH3 constant region comprising three mutations (S228P, F234A and L235A) was created. The amplified fusion gene was ligated to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of a trastuzumab-coil-based fusion protein. Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 33: trastuzumab-coil- hEPO Expression and purification of fusion proteins

Trastuzumab-coil-hEPO based fusion protein was expressed by transient transfection of free HEK293 cells with vectors encoding the trastuzumab-coil-hEPO fusion protein heavy chain and trastuzumab light chain (SEQ ID NO: 1). The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. Fusion proteins were purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel. As shown in Figure 26, lane 1 depicts the protein ladder. Lane 2 depicts purified trastuzumab-coil-hEPO (CDRH3) and trastuzumab LCs, and lane 3 depicts trastuzumab-coil-hEPO (CDRH3) and DTT treated trastuzumab LCs.

Example 34: trastuzumab-coil- hEPO Electrospray Ionization Mass Spectrometry (ESI-MS) of Based Fusion Proteins

10 μg of purified trastuzumab-coil-hEPO (CDRH3) in PBS (pH 7.4) was treated with 1 μl (500 units) of peptide-N-glucosidase (NEB) at 37° C. overnight, followed by 50 mM DTT was added. Fusion proteins were analyzed by ESI-MS using Agilent Technology's 6520 Q-TOF LC/MS. A chromatograph is shown in [FIG. 27]. The expected molecular weight of trastuzumab-coil-hEPO (CDRH3) HC is 70,307 Da. The measured molecular weight of trastuzumab-coil-hEPO (CDRH3) HC was 70,177 Da. The measured molecular weight is associated with O-glycosylation of hEPO and the absence of the first amino acid glutamic acid (E).

Example 35: HER2 Trastuzumab-coil for receptors hEPO Binding of based fusion proteins

HER2-overexpressing SKBR3 cells were cultured in DMEM containing 10% FBS and 1% penicillin and streptomycin. Cells were washed 3 times with cold PBS, blocked with 2% BSA in PBS, and incubated with 10 or 100 nM of trastuzumab and trastuzumab-coil-hEPO (CDRH3) at 4° C. for 2 hours with gentle mixing. . Unbound antibody was removed by washing with 2% BSA in PBS. Thereafter, the cells were stained with FITC anti-human IgG Fc (KPL, Inc., MD) with gentle mixing at 4° C. for 1 hour, washed with PBS, and analyzed by flow cytometry. 28 depicts a flow cytometry histogram.

Example 36: TF -1 trastuzumab-coil- against cells hEPO In vitro proliferative activity assay of fusion proteins

Human TF-1 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS), penicillin and streptomycin (50 U/mL), and 2 ng/ml human granulocyte macrophage colony stimulating factor (GM-CSF). Incubated at 37° C. under 5% CO ₂ . To investigate the proliferative activity of the trastuzumab-hEPO fusion protein, the cells were washed three times with RPMI-1640 medium containing 10% FBS and 1.5×10 ⁵ cells/ml in RPMI-1640 medium containing 10% FBS. Resuspended to density, hEPO, trastuzumab, and trastuzumab-coil hEPO (CDRH3) fusion proteins were plated in 96-well plates (1.5×10 ⁴ cells/ml per well) at various concentrations, followed by 5% CO ₂ Incubated for 72 hours at 37 ° C. Thereafter, the cells were treated with Alamar Blue (Invitrogen) at 37° C. for 4 hours. The fluorescence intensity measured at 595 nm is proportional to cell viability. Logistic sigmoidal function: y = A2 + (A1-A2)/(1 + (x/x0)p), where A1 is the initial value, A2 is the final value, and x0 is the inflection point of the curve. , and p is power) to determine the EC ₅₀ value. [Fig. 29] is a graph showing data. The EC ₅₀ of hEPO was 0.1 + 0.02 nM. The EC ₅₀ of Trastuzumab-coil hEPO (CDRH3) was 0.1 + 0.01 nM.

Example 37: trastuzumab hGCSF Construction of /EPO double fusion protein

The gene encoding hEPO (SEQ ID NO: 192) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the immunoglobulin fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the hEPO fragment. Sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), which form antiparallel coiled coils, were then added to the ends of the N- and C-terminal ends of the bEPO-linker fragment. Subsequently, a PCR fragment encoding the hEPO gene having an extender peptide and a linker was grafted into the complementarity determining region 3 (CDRH3) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to replace the Thr99-Met107 loop. Trastuzumab-coil hEPO (CDRH3) HC by replacing the CH1-CH3 constant region of the Trastuzumab-coil hEPO (CDRH3) heavy chain with a human IgG4 CH1-CH3 constant region comprising three mutations (S228P, F234A and L235A) (SEQ ID NO: 62).

The gene encoding human GCSF (hGCSF) (SEQ ID NO: 187) was synthesized by Genescript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the hGCSF fragment. Sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), forming antiparallel coiled coils, were then added to the ends of the N- and C-terminal ends of the bGCSF-linker fragment. A PCR fragment encoding the hGCSF-linker-extender peptide was grafted into the complementarity determining region 3 (CDRL3) of the light chain of the trastuzumab IgG antibody using overlap extension PCR to replace Thr93-Pro95. Trastuzumab-coil-hGCSF based fusion protein was modified to have human hIgG1 CH1-CH3 constant region comprising 7 mutations (E233P, L234V, L235A, AG236, A327G, A330S, and P331S) to trastuzumab-coil hGCSF (CDRL3) LC (SEQ ID NO: 63) was generated. The amplified fusion gene was ligated in-frame to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of the trastuzumab-coil-based fusion protein.

Example 38: trastuzumab hGCSF Expression and purification of /EPO double fusion protein

Trastuzumab- Coil-hGCSF/EPO double fusion protein was expressed. The expressed double fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. Fusion proteins were purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel. As shown in FIG. 30 , lane 1 shows the protein ladder, lane 2 shows trastuzumab-coil-hGCSF/EPO double fusion protein, and lane 3 shows DTT treated trastuzumab-coil-hGCSF The /EPO double fusion protein is shown.

Example 39: trastuzumab hGCSF / hEPO Electrospray Ionization Mass Spectrometry (ESI-MS) of Based Fusion Proteins

10 μg of purified trastuzumab-coil-hGCSF/EPO double fusion protein (SEQ ID NOs: 62, 63) in PBS (pH 7.4) was treated with 1 μl (500 units) of peptide-N-glucosidase (NEB) 37 After overnight treatment at °C, 50 mM DTT was added. Fusion proteins were analyzed by ESI-MS using Agilent Technology's 6520 Q-TOF LC/MS. A chromatograph is shown in [FIG. 31(A)]. The expected molecular weight of trastuzumab-coil hGCSF (CDRL3) LC is 45,746 Da. The measured molecular weight of trastuzumab-coil hGCSF (CDRL3) LC was 46,690 Da. The measured molecular weight correlates with O-glycosylation of hGCSF.

10 μg of trastuzumab-coil-hGCSF/EPO double fusion protein (SEQ ID NOs: 62, 63) in PBS (pH 7.4) with 1 μl (500 units) of peptide-N-glucosidase (NEB) at 37° C. After overnight treatment, 50 mM DTT was added. Fusion proteins were analyzed by ESI-MS using Agilent Technology's 6520 Q-TOF LC/MS. A chromatograph is shown in [FIG. 31(B)]. The expected molecular weight of trastuzumab-coil hEPO (CDRH3) HC is 70,307 Da. The measured molecular weights of Trastuzumab-coil-hEPO (CDRH3) HC are 70,179 Da (correlated with the mass of Trastuzumab-coil hEPO (CDRH3) HC without the first amino acid glutamic acid) and 71,126 Da (O-glycosylation of hEPO) associated with).

Example 40: HER2 for the receptor Trastuzumab hGCSF / hEPO base Binding of fusion proteins

HER2-overexpressing SKBR3 cells were cultured in DMEM containing 10% FBS and 1% penicillin and streptomycin. Cells were washed 3 times with cold PBS, blocked with 2% BSA in PBS, and with 10 or 100 nM of trastuzumab and trastuzumab-coil-hGCSF/EPO double fusion proteins (SEQ ID NOs: 62, 63) at 4°C. Incubated with gentle mixing for 2 hours. Unbound antibody was removed by washing with 2% BSA in PBS. Thereafter, the cells were stained with FITC anti-human IgG Fc (KPL, Inc., MD) with gentle mixing at 4° C. for 1 hour, washed with PBS, and analyzed by flow cytometry. 32 depicts a flow cytometry histogram.

Example 41: TF Trastuzumab on -1 cells hGCSF / hEPO In vitro proliferative activity of fusion proteins

Human TF-1 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS), penicillin and streptomycin (50 U/mL), and 2 ng/ml human granulocyte macrophage colony stimulating factor (GM-CSF). Incubated at 37° C. under 5% CO ₂ . To investigate the proliferative activity of trastuzumab hGCSF/hEPO fusion protein, cells were washed three times with RPMI-1640 medium containing 10% FBS and 1.5×10 ⁵ cells/ ml density, hEPO, trastuzumab, and trastuzumab hGCSF/hEPO (CDRH3) fusion proteins (SEQ ID NOs: 62, 63) at various concentrations in 96-well plates (1.5×10 ⁴ cells/ml per well) After plate incubation at 37° C. under 5% CO ₂ for 72 hours. Thereafter, the cells were treated with Alamar Blue (Invitrogen) at 37° C. for 4 hours. The fluorescence intensity measured at 595 nm is proportional to cell viability. [Fig. 33] is a graph showing data. The EC ₅₀ of hEPO was 0.1 + 0.02 nM. The EC ₅₀ of Trastuzumab-coil hGCSF/hEPO was 0.2 + 0.03 nM.

Example 42: Trastuzumab-coil on mouse NFS-60 cells hGCSF / hEPO In vitro study of fusion protein proliferative activity

Mouse NFS-60 cells were cultured in RPMI-1640 medium supplemented with 10% FBS, 0.05 mM 2-mercaptoethanol and 62 ng/ml human macrophage colony stimulating factor (M-CSF). To investigate the proliferative activity of the trastuzumab hGCSF/hEPO fusion protein, the cells were washed three times with RPMI-1640 medium containing 10% FBS, and RPMI- containing 10% FBS and 0.05 mM 2-mercaptoethanol. Resuspended in 1640 medium at a density of 1.5×10 ⁵ cells/ml, hGCSF, trastuzumab, and trastuzumab hGCSF/hEPO (CDRH3) fusion proteins (SEQ ID NOs: 62, 63) were mixed in 96-well plates (per well) at various concentrations. 1.5×10 ⁴ cells/ml) and incubated for 72 hours at 37° C. under 5% CO ₂ . Thereafter, the cells were treated with Alamar Blue (Invitrogen) at 37° C. for 4 hours. The fluorescence intensity measured at 595 nm is proportional to cell viability. [Fig. 34] shows the data graphically. The EC ₅₀ of hGCSF was 1.7 + 0.3 nM. The EC ₅₀ of Trastuzumab-coil hGCSF/hEPO was 3.1 + 0.1 nM.

Example 43: Herceptin for expression in mammalian cells hGH Construction of fusion protein vectors

The gene encoding hGH (SEQ ID NO: 201) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the immunoglobulin fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the hGH fragment. To generate the Herceptin-coil hGH fusion protein, the sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), which form antiparallel coiled coils, were added to the N- and C of the hGH-linker fragment. - was added at the end of the end. To generate the trastuzumab-direct hGH (CDRH2) fusion protein (SEQ ID NO: 128), a PCR fragment encoding the hGH gene with a linker was combined with the complementarity determining region 2 (CDRH2) of the heavy chain of the Herceptin IgG antibody using overlap extension PCR. ) was transplanted. To generate the trastuzumab-coil hGH (CDRH3) fusion protein (SEQ ID NO: 75), a PCR fragment encoding the hGH gene with an extender peptide and a linker was used overlap extension PCR to determine the complementarity determining region of the heavy chain of the Herceptin IgG antibody. 3 (CDRH3). To generate the trastuzumab-coil hGH (CDRH2) fusion protein (SEQ ID NO: 76), a PCR fragment encoding the hGH gene with an extender peptide and a linker was used overlap extension PCR to determine the complementarity determining region of the heavy chain of the Herceptin IgG antibody. 2 (CDRH2). The amplified fusion gene was ligated in-frame to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of the trastuzumab hGH-based fusion protein. The obtained expression vector was confirmed by DNA sequencing.

Example 44: trastuzumab hGH Expression and purification of based fusion proteins

Trastuzumab-direct hGH based fusion protein by transient transfection of free HEK293 cells with vectors encoding trastuzumab-direct hGH (CDRH2) HC (SEQ ID NO: 128), and trastuzumab light chain (SEQ ID NO: 19) was expressed. Trastuzumab-coil hGH (CDRH3) by transient transfection of free HEK293 cells with vectors encoding trastuzumab-coil hGH (CDRH3) HC (SEQ ID NO: 75), and trastuzumab light chain (SEQ ID NO: 19) The base fusion protein was expressed. Trastuzumab-coil hGH (CDRH2) by transient transfection of free HEK293 cells with vectors encoding trastuzumab-coil hGH (CDRH2) HC (SEQ ID NO: 76), and trastuzumab light chain (SEQ ID NO: 19) The base fusion protein was expressed. The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. Fusion proteins were purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel. As shown in Figure 35, lane 1 shows the protein ladder, lane 2 shows trastuzumab-coil hGH (CDRH3) (SEQ ID NOs: 75, 19), lane 3 shows DTT treated trastuzumab - shows coil hGH (CDRH3) (SEQ ID NOs: 75, 19), lane 4 shows the protein ladder, lane 5 shows trastuzumab-direct hGH (CDRH2) (SEQ ID NOs: 128 and 19), lane 6 depicts DTT treated trastuzumab-direct hGH (CDRH2) (SEQ ID NOs: 128 and 19), lane 7 depicts trastuzumab-coil hGH (CDRH2) (SEQ ID NOs: 76, 19), lane 8 shows DTT treated trastuzumab-coil hGH (CDRH2) (SEQ ID NOs: 76, 19).

Example 45: trastuzumab hGH based fusion protein activity assay

bGHR-Ba/F3 proliferation assay: A mouse Ba/F3 cell line was stably transduced with the hGH receptor (hGHR) under the EF1α promoter. The cloned hGHR-Ba/F3 was maintained in 10% FBS, RPMI1640, and 50 ng/mL of hGH. Proliferation assays were performed in 96-well culture plates containing 20,000 cells in 200 μl assay medium (10% FBS in RPMI1640) per well. Increasing concentrations of hGH, trastuzumab-coil hGH (CDRH3), trastuzumab-coil hGH (CDRH2), and trastuzumab-direct bGH (CDRH2) were incubated with cells for 72 hours. At the end of the incubation period, 20 μl of Prestoblue was added to each well and the fluorescence signal was recorded at 590 nm under 550 nm excitation in a Spectramax fluorescence plate reader. The EC ₅₀ values of hGH and trastuzumab hGH fusions are shown in Table 15.

NB2 Proliferation Assay: The rat Nb2-11 cell line (Sigma) was maintained in 10% FBS, 10% horse serum (HS) in RPMI with 55 μM β-ME. Proliferation assays were performed in 96-well culture plates containing 50,000 cells in 200 μl per well of assay medium (10% HS in RPMI with 55 uM β-ME). Increasing concentrations of hGH, trastuzumab-coil hGH (CDRH3), trastuzumab-coil hGH (CDRH2), and trastuzumab-direct bGH (CDRH2) were incubated with cells for 72 hours. At the end of the incubation period, 20 μl of Prestoblue was added to each well and the fluorescence signal was recorded at 590 nm under 550 nm excitation in a Spectramax fluorescence plate reader. The EC ₅₀ values of hGH and trastuzumab hGH fusions are shown in Table 15.

Stat5 phosphorylation assay: Human IM9 cells (ATCC) were maintained in 10% FBS in RPMI1640. The night before the phosphorylation assay, 2×10e ⁵ IM9 cells were seeded in 200 μl assay medium (1% charcoal stripped FBS in RPMI) in V bottom 96 well plates and starved overnight. On the day of the phosphorylation experiment, starvation cells were stimulated with varying concentrations of hGH, trastuzumab-coil hGH (CDRH3), trastuzumab-coil hGH (CDRH2), and trastuzumab-direct bGH (CDRH2) at 37°C for 10 min. did After stimulation, cells were fixed with 4% formaldehyde at 37° C. for 10 minutes, and then permeabilized with 90% methanol. Cells were then blocked with 5% BSA for 10 min at room temperature and then prepared with Alexa Fluor® 488-conjugated anti-pStat5(Tyr694)(C71E5) rabbit mAb (Cell Signaling Technology, Inc.) Stained according to the protocol presented in Cells were washed with PBS and analyzed by flow cytometry. The EC ₅₀ of hGH and trastuzumab hGH fusions are shown in Table 15.

[Table 15]

Example 46: Trastuzumab-coil hGH ( CDRH3 ) drug dynamics research

Trastuzumab-coil hGH (CDRH3) and genotropin at 2 mg/kg in PBS were injected intravenously (iv) or subcutaneously (sc) into 3 SD female rats per treatment divided into 2 treatment groups. . Plasma samples were withdrawn at 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 3 days, 4 days, 7 days, 10 days, and 14 days. The amount of genotropin was quantified by the hGH Human Direct ELISA Kit (Life Technologies). Trastuzumab-coil hGH (CDRH3) was quantified by a sandwich ELISA assay. Briefly, maxisorb ELISA plates were coated with goat anti-human IgG Fc (Abcam, ab98616) at 37° C. for 1 h and then blocked with 5% BSA. Appropriately diluted plasma was added to the blocked wells and the wells were incubated for 1 hour at room temperature. After washing the wells, biotinylated polyclonal anti-hGH antibody (R&D systems, BAF1067) was applied to the wells for 1 hour. Plates were washed and incubated with a high-sensitivity streptavidin-HRP conjugate (Pierce, 21130) at room temperature for 1 hour. After several washes, QuantaBlu fluorogenic ELISA substrate was applied and the signal was acquired with a Spectramax fluorescence plate reader. The amount of trastuzumab-coil hGH (CDRH3) fusion in plasma samples was quantified by extrapolating the signal to the linear range of the standard curve (signal vs concentration). The concentrations of genotropin and trastuzumab-coil hGH (CDRH3) at each collection time point were plotted and shown in FIG. 36 . [Fig. 36A] shows the pharmacokinetics by intravenous injection. [Fig. 36 B] shows the pharmacokinetics by subcutaneous injection.

Example 47: Trastuzumab-coil hGH ( CDRH3 ) drug kinetics research

The pharmacokinetic performance of the trastuzumab-coil hGH (CDRH3) fusion was evaluated in a standard hypopituitized rat assay. Pituitary resected male rats were purchased from Harlan and pre-screened several days prior to study to monitor body weight normalization after surgery/travel. Initial body weight-matched rats were treated with one of several regimens: genotropin daily subcutaneous injection (0.1 mg/kg) for 14 days; or biweekly administration of genotropin (0.3 mg/kg) or trastuzumab-coil hGH (CDRH3) (1.0 mg/kg). Animals were weighed daily. At the end of the treatment period, animals were sacrificed and epiphyseal thickness was measured. The rate of change of body weight from day 1 was plotted daily and is shown in FIG. 37 .

Example 48: Trastuzumab-coil for expression in mammalian cells h leptin Construction of based fusion protein vectors

The gene encoding hleptin (SEQ ID NO: 197) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of the immunoglobulin fusion protein, a flexible linker GGGGS (SEQ ID NO: 179, n=1) was added to both ends of the hleptin fragment. Sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), which form antiparallel coiled coils, were then added to the ends of the N- and C-terminal ends of the hleptin-linker fragment. A PCR fragment encoding the hleptin gene having an extender peptide and a linker was grafted into the complementarity determining region 3 (CDRH3) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR. Trastuzumab-coil hleptin (CDRH3) by modifying the constant region of Trastuzumab to have a human hIgG1 CH1-CH3 constant region comprising 7 mutations (E233P, L234V, L235A, AG236, A327G, A330S, and P331S) HC (SEQ ID NO: 78) was generated. To generate the CDRL3 fusion, a PCR fragment encoding the hleptin gene having an extender peptide and a linker was grafted into the complementarity determining region 3 (CDRL3) of the light chain of the Trastuzumab IgG antibody using overlap extension PCR to generate Thr93-Pro95. Substituted and generated trastuzumab-coil hleptin (CDRL3) (SEQ ID NO: 49). A PCR fragment encoding the hleptin gene having an extender peptide and a linker was grafted into the complementarity determining region 2 (CDRH2) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to trastuzumab-coil h leptin (CDRH2) HC (SEQ ID NO: 79). The amplified fusion gene was ligated to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of a trastuzumab-coil hleptin-based fusion protein. Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 49: trastuzumab-coil h leptin Expression and purification of based fusion proteins

Trastuzumab-coil hLeptin (CDRH3) by transient transfection of free HEK293 cells with vectors encoding trastuzumab-coil hleptin (CDRH3) HC (SEQ ID NO: 78) and trastuzumab light chain (SEQ ID NO: 19) ) based fusion proteins were expressed. Trastuzumab-coil hLeptin (CDRH2) by transient transfection of free HEK293 cells with vectors encoding trastuzumab-coil hleptin (CDRH2) HC (SEQ ID NO: 79) and trastuzumab light chain (SEQ ID NO: 19) ) based fusion proteins were expressed. Trastuzumab-coil hleptin (CDRL3) by transient transfection of free HEK293 cells with vectors encoding trastuzumab-coil hleptin (CDRL3) LC (SEQ ID NO: 49) and trastuzumab heavy chain (SEQ ID NO: 4). ) based fusion proteins were expressed. The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. Fusion proteins were purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel. 38 , lane 1 depicts trastuzumab-coil h leptin (CDRH2) (SEQ ID NOs: 79, 19), and lane 2 depicts DTT-treated trastuzumab-coil h leptin (CDRH2) ( SEQ ID NOs: 79, 19), lanes 3, 4 and 7 depict protein molecular weight markers, lane 5 depicts trastuzumab-coil hleptin (CDRH3) (SEQ ID NOs: 78, 19), lane 6 depicts DTT treated trastuzumab-coil hleptin (CDRH3) (SEQ ID NOs: 78, 19), lane 8 depicts trastuzumab-coil hleptin (CDRL3) (SEQ ID NOs: 49, 4), lane 9 depicts DTT treated trastuzumab-coil hleptin (CDRL3) (SEQ ID NOs: 49, 4).

Example 50: human leptin receptor ( LepR ) trastuzumab-coil on activation h leptin In vitro activity of based fusion proteins

Baf3 stable cells overexpressing human leptin receptor (LepR) were seeded in 96-well plates, hleptin (SEQ ID NO: 238), trastuzumab-coil h leptin (CDRH2) (SEQ ID NOs: 79, 19), and trastuz Zumab-coil hleptin (CDRH3) (SEQ ID NOs: 78, 19) was treated at different doses for 72 hours. Alamarblue reagent was added in 1/10 volume, incubated for 2 hours, and fluorescence was measured at 590 nm under 560 nm excitation. Data were analyzed using GraphPad Prism 6 (GraphPad Prism 6). [Fig. 39] is a graph showing data. The EC ₅₀ of h leptin was 129.4 + 46.09 pM ( FIG. 39A ). The EC ₅₀ of trastuzumab-coil h leptin (CDRH3) was 55.38 + 14.04 pM. The EC ₅₀ of trastuzumab-coil h leptin (CDRH2) was 99.41 + 18.91 pM. The EC ₅₀ of h leptin was 58.19 + 10.88 pM ( FIG. 39B ). The EC ₅₀ of trastuzumab-coil h leptin (CDRL3) was 665.1 + 62.70 pM.

Example 51: Trastuzumab-coil h leptin base of the fusion protein SKBR3 Combination

SKBR3 cells were cultured in DMEM containing 10% FBS and 1% penicillin and streptomycin. Cells were washed 3 times with cold PBS, blocked with 2% BSA in PBS, and trastuzumab at 10 or 100 nM, trastuzumab-coil hleptin (CDRH2) (SEQ ID NOs: 79, 19), and trastuzumab -Coil h-leptin (CDRH3) (SEQ ID NOs: 78, 19) was incubated with gentle mixing at 4° C. for 2 hours. Unbound antibody was removed by washing with 2% BSA in PBS. Thereafter, the cells were stained with FITC anti-human IgG Fc (KPL, Inc., MD) with gentle mixing at 4° C. for 1 hour, washed with PBS, and analyzed by flow cytometry. 40 depicts flow cytometry histograms of (A) trastuzumab, (B) trastuzumab-coil hleptin (CDRH2), and (C) trastuzumab-coil hleptin (CDRH3).

Example 52: Trastuzumab-coil- for expression in mammalian cells elaphine Construction of fusion protein vectors

The gene encoding elaffin (SEQ ID NO: 217) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). A flexible GGGGS linker (SEQ ID NO: 179) was added to the N-terminus and C-terminus of the elafin gene fragment to increase the folding and stability of the fusion protein. Sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), which form antiparallel coiled coils, were then added to the ends of the N- and C-terminal ends of the elastin linker fragment. Subsequently, a PCR fragment encoding elaffin with a linker and an extension fragment was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to replace the Trp99-Met107 loop. Trastuzumab-coil-elaffin based fusion protein was modified to have human hIgG1 CH1-CH3 constant region comprising 7 mutations (E233P, L234V, L235A, AG236, A327G, A330S, and P331S) to trastuzumab-coil -Elapin HC fusion (SEQ ID NO: 54) was generated. The amplified fusion gene was ligated to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of trastuzumab-coil-elafin (CDRH3). Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 53: trastuzumab-coil- elaphine Expression and purification of based fusion proteins

Trastuzumab-coil-elaffin (CDRH3) by transient transfection of free HEK293 cells with vectors encoding trastuzumab-coil elaffin fusion protein heavy chain (SEQ ID NO: 54) and trastuzumab light chain (SEQ ID NO: 19) ) based fusion proteins were expressed. The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. The fusion protein was purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel as shown in FIG. 41 . Lane 1 is a protein marker. Lane 2 is Trastuzumab-coil-elafin (CDRH3) IgG (SEQ ID NOs: 85 and 19). Lane 3 is DTT treated trastuzumab-coil-elafin (CDRH3) IgG (SEQ ID NOs: 85 and 19).

Example 54: Elastase Inhibition Assay

Human elastase was purchased from Elastin Products Company, Inc. Increasing concentrations of elafin (SEQ ID NO: 258) and trastuzumab-coil elafin (CDRH3) IgG (SEQ ID NOs: 85 and 19) were incubated with elastase at room temperature, and the residual activity of elastase was reduced to fluorogenic elastin. Starase substrate MeOSuc-AAPV-AMC (EMD Millipore) was added and analyzed. Response slopes were obtained by monitoring the 420 nm wavelength under 325 nm excitation using a SpectraMax fluorescence plate reader. Each data point was replicated three times to fit the equation below.

Q=(Ki*(1+(S/Km))).

Y=Vo*(1-((((Et+X+Q)-(((Et+X+Q)^2)-4*Et*X)^0.5))/(2*Et))). Figure 42 shows elastase inhibition by elafin (A) and trastuzumab-coil elafin (CDRH3) IgG (B).

Example 55: Trastuzumab-coil for expression in mammalian cells GLP2 Construction of fusion protein vectors

The gene encoding GLP2 (SEQ ID NO: 222) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). A flexible CGGGGS linker (SEQ ID NO: 276) was added to the N-terminus of GLP2 and a flexible GGGGSC (SEQ ID NO: 277) was added to the C-terminus of GLP2. Then, sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), which form antiparallel coiled coils, were added to the ends of the N- and C-terminal ends of the GLP2 linker fragment. Subsequently, a PCR fragment encoding GLP2 having a linker and an extension fragment was grafted into the complementarity determining region 3 (CDR3H) of the trastuzumab IgG antibody using overlap extension PCR to replace the Trp99-Met107 loop. Trastuzumab-coil GLP2 based fusion protein was modified to have a human hIgG1 CH1-CH3 constant region comprising 7 mutations (E233P, L234V, L235A, AG236, A327G, A330S, and P331S) to have Trastuzumab-coil GLP2 ( CDRH3) HC fusion (SEQ ID NO: 65) was generated. The amplified fusion gene was ligated to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of trastuzumab-coil GLP2 (CDRH3). Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 56: Trastuzumab-coil GLP2 Expression and purification of based fusion proteins

Trastuzumab-coil GLP2 fusion proteins Trastuzumab-coil GLP2 (CDRH3) based fusion by transient transfection of free HEK293 cells with vectors encoding the heavy chain (SEQ ID NO: 65) and trastuzumab light chain (SEQ ID NO: 19) protein was expressed. The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. The fusion protein was purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel as shown in FIG. 43 . Lane 1 is a protein marker. Lane 2 is Trastuzumab-coil GLP2 (CDRH3) IgG (SEQ ID NOs: 96 and 19). Lane 3 is DTT treated trastuzumab-coil GLP2 (CDRH3) IgG (SEQ ID NOs: 96 and 19).

Example 57: Construction of trastuzumab-coil relaxin (insulin c-peptide) fusion protein vector for expression in mammalian cells

The gene encoding relaxin (insulin c peptide) (SEQ ID NO: 225) was synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). A flexible GGGGS linker (SEQ ID NO: 179) was added to the N-terminus of relaxin and flexible GGGGS (SEQ ID NO: 179) was added to the C-terminus of relaxin. Then, sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), forming antiparallel coiled coils, were added to the ends of the N- and C-terminal ends of the relaxin linker fragment. Subsequently, a PCR fragment encoding relaxin (insulin c-peptide) having a linker and an extension fragment was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR, and Trp99-Met107 The loop was replaced. Trastuzumab-coil relaxin (insulin c-peptide) based fusion protein was modified to have human hIgG1 CH1-CH3 constant region containing 7 mutations (E233P, L234V, L235A, AG236, A327G, A330S, and P331S) Trastuzumab-coil relaxin (insulin c-peptide) (CDRH3) HC fusions were generated. The amplified fusion gene was ligated to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of trastuzumab-coil relaxin (insulin c-peptide) (CDRH3). Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 58: trastuzumab-coil relaxin Expression and purification of (insulin c-peptide) based fusion proteins

Trastuzumab-coil relaxin (insulin c-peptide) ( CDRH3) based fusion protein was expressed. The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. The fusion protein was purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel as shown in FIG. 44 . Lane 1 is DTT treated trastuzumab-coil relaxin (insulin c-peptide) (CDRH3) IgG. Lane 2 is trastuzumab-coil relaxin (insulin c-peptide) (CDRH3) IgG. Lane 3 is a protein marker.

Example 59: Trastuzumab-coil for expression in mammalian cells relaxin Construction of fusion protein vectors

Genes encoding relaxin containing the internal protease cleavage sites of factors Xa and PC2 (IEGRKKR (SEQ ID NO: 278)) were synthesized by GeneScript or IDT and amplified by polymerase chain reaction (PCR). A flexible GGGGS linker (SEQ ID NO: 179) was added to the N-terminus of relaxin and flexible GGGGS (SEQ ID NO: 179) was added to the C-terminus of relaxin. Then, sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), forming antiparallel coiled coils, were added to the ends of the N- and C-terminal ends of the relaxin linker fragment. Subsequently, a PCR fragment encoding relaxin having a protease cleavage site, a linker and an extension fragment was grafted into the complementarity determining region 3 of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to replace the Trp99-Met107 loop. Trastuzumab-coil relaxin based fusion protein was modified to have human hIgG1 CH1-CH3 constant region comprising 7 mutations (E233P, L234V, L235A, AG236, A327G, A330S, and P331S) to trastuzumab-coil reel Lexin (CDRH3) HC fusions were generated. The amplified fusion gene was ligated to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of trastuzumab-coil relaxin (CDRH3). Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 60: trastuzumab-coil relaxin Expression and purification of based fusion proteins

Trastuzumab-coil relaxin (CDRH3) by transient transfection of free HEK293 cells with vectors encoding trastuzumab-coil relaxin fusion protein heavy chain (SEQ ID NO: 90) and trastuzumab light chain (SEQ ID NO: 18) The base fusion protein was expressed. The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. The fusion protein was purified by protein A/G chromatography (Thermo Fisher Scientific, IL) and analyzed by SDS-PAGE gel as shown in FIG. 45 . Lane 1 is a protein marker. Lane 2 is trastuzumab-coil relaxin (CDRH3) IgG. Lane 3 is DTT treated trastuzumab-coil relaxin (CDRH3) IgG. Lane 4 is trastuzumab-coil relaxin (CDRH3) IgG co-expressed with protease PC2. Lane 5 is trastuzumab-coil relaxin (CDRH3) IgG co-expressed with PC2 and treated with DTT.

Example 61: Trastuzumab-coil for expression in mammalian cells relaxin XTEN35 ) Construction of the fusion protein vector

The gene (SEQ ID NO: 224) encoding relaxin (XTEN35) comprising an internal 6x HIS (SEQ ID NO: 274) and a PC2 protease cleavage site (RKKR) was synthesized by GenScript or IDT, and polymerase chain reaction (PCR) was amplified by A flexible GGGGS linker (SEQ ID NO: 179) was added to the N-terminus of relaxin (XTEN35) and flexible GGGGS (SEQ ID NO: 179) was added to the C-terminus of relaxin (XTEN35). Sequences encoding the extender peptides GGSGAKLAALKAKLAALK (SEQ ID NO: 151) and ELAALEAELAALEAGGSG (SEQ ID NO: 161), forming antiparallel coiled coils, were then added to the ends of the N- and C-terminal ends of the relaxin (XTEN35) linker fragment. did Subsequently, a PCR fragment encoding relaxin (XTEN35) having a linker and an extension fragment was grafted into the complementarity determining region 3 (CDR3H) of the heavy chain of the trastuzumab IgG antibody using overlap extension PCR to replace the Trp99-Met107 loop. did Trastuzumab-coil relaxin (XTEN35) based fusion protein was modified to have human hIgG1 CH1-CH3 constant region containing 7 mutations (E233P, L234V, L235A, AG236, A327G, A330S, and P331S) to trastuzumab -Coil relaxin (CDRH3) HC fusions were generated. The amplified fusion gene was ligated to the pFuse backbone vector (InvivoGen, CA) to generate an expression vector of trastuzumab-coil relaxin (CDRH3). Similarly, the gene encoding the light chain of the Trastuzumab IgG antibody (SEQ ID NO: 1) was cloned into the pFuse backbone vector. The obtained expression vector was confirmed by DNA sequencing.

Example 62: trastuzumab-coil relaxin ( XTEN35 ) expression and purification of based fusion proteins

Trastuzumab-coil relaxin (XTEN35) fusion protein A trastuzumab-coil relaxin (XTEN35) (CDRH3) based fusion protein was obtained by transiently transfecting free HEK293 cells with vectors encoding the heavy chain and trastuzumab light chain. manifested. The expressed fusion protein was secreted into the culture medium and recovered 48 and 96 hours after transfection. The fusion protein was purified by protein A/G chromatography (Thermo Fisher Scientific, IL), digested with protease PC2, and analyzed by SDS-PAGE gel as shown in FIG. 46 . Lane 1 is DTT treated trastuzumab-coil relaxin (XTEN35) (CDRH3) IgG. Lane 2 is trastuzumab-coil relaxin (XTEN35) (CDRH3) IgG. Lane 3 is trastuzumab-coil relaxin (XTEN35) (CDRH3) IgG co-expressed with PC2 and treated with DTT. Lane 4 is Trastuzumab-coil relaxin (XTEN35) (CDRH3) IgG co-expressed with PC2. Lane 5 is a protein molecular weight marker.

Example 63: Her2 Trastuzumab-coil- to receptor hGCSF binding of proteins

The binding affinity of the trastuzumab-coil-hGCSF fusion protein to the Her2 receptor is investigated by ELISA. Human Her2-Fc chimeras (5 μg/mL) (R&D Systems) are coated overnight at 4° C. in 96-well ELISA plates and then blocked with 1% BSA in PBS (pH 7.4) at 37° C. for 2 h. After washing with 0.05% Tween-20 in PBS (pH 7.4), various concentrations of trastuzumab IgG and trastuzumab-coil-hGCSF fusion protein are added to the plate and incubated at 37° C. for 2 hours. Subsequently, a goat polyclonal anti-human kappa light chain antibody with HRP conjugate (Sigma) is added to the plate and the plate is incubated at 37° C. for 2 hours. Subsequently, the wells are washed and a fluorogenic peroxidase substrate is added to each well to examine the binding affinity based on the fluorescence intensity at 425 nm.

Example 64: Her2 Binding of Trastuzumab-Coil-VM24 to Receptor

The binding affinity of the trastuzumab-coil-VM24 fusion protein to the Her2 receptor is investigated by ELISA. Human Her2-Fc chimera (5 μg/mL) (R&D Systems) is coated in 96-well ELISA plates overnight at 4° C. and then blocked with 1% BSA in PBS (pH 7.4) at 37° C. for 2 h. After washing with 0.05% Tween-20 in PBS (pH 7.4), various concentrations of trastuzumab IgG and trastuzumab-coil-VM24 fusion protein are added to the plate and incubated at 37° C. for 2 hours. Subsequently, a goat polyclonal anti-human kappa light chain antibody with HRP conjugate (Sigma) is added to the plate and the plate is incubated at 37° C. for 2 hours. Subsequently, the wells are washed and a fluorogenic peroxidase substrate is added to each well to examine the binding affinity based on the fluorescence intensity at 425 nm.

Example 65: trastuzumab-coil h leptin - exendin -4 Construction of the double fusion protein

Leptin and exendin-4 are fused to the CDR-3H and CDR-3L regions in the trastuzumab framework with engineered coiled coil stems. The resulting, biologically active humanized fusion protein may have improved pharmacological properties for the treatment of the disease in question. In addition, the combination of h leptin and Ex-4 may show a synergistic effect. The trastuzumab-coil h leptin/Ex4 fusion consists of a GGGGS linker (SEQ ID NO: 179) at each end of the fused h leptin and Ex-4 fragment and a GGSG linker (SEQ ID NO: 279) connecting the coiled coil to the base of the antibody. include

Example 66: Her2 Trastuzumab-coil-mocha for receptors IgG Combination

Binding of the trastuzumab-coil-Mocha fusion protein to the Her2 receptor is investigated by ELISA. Human Her2-Fc chimera (5 μg/mL) (R&D Systems) is coated in 96-well ELISA plates at 4° C. overnight, followed by blocking with 1% BSA in PBS (pH 7.4) at 37° C. for 2 h. After washing with 0.05% Tween-20 in PBS (pH 7.4), various concentrations of Trastuzumab IgG and Trastuzumab-Coil-Mocha fusion protein are added to each well and the plate is incubated at 37° C. for 2 hours. Subsequently, a goat polyclonal anti-human kappa light chain antibody with HRP conjugate (Sigma) is added to the plate and the plate is incubated at 37° C. for 2 hours. Subsequently, the wells are washed and a fluorogenic peroxidase substrate is added to each well to examine the binding affinity based on the fluorescence intensity at 425 nm.

The foregoing merely illustrates the principles of the invention. It will be appreciated that, although not explicitly described or shown herein, those skilled in the art will be able to devise various arrangements that encompass the principles and are included within the spirit and scope of the invention. Moreover, language representing all embodiments and conditions listed herein is primarily intended to help the reader understand the principles and concepts of the invention contributed by the inventor to the advancement of the art, wherein the specifically enumerated embodiment and conditions are not to be construed as limiting. Moreover, all recitations of principles, aspects, and embodiments of the invention, as well as specific embodiments thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, the above equivalents are intended to include both currently known equivalents and equivalents developed in the future, ie, all elements developed to perform the same function, regardless of structure. Accordingly, it is not intended to limit the scope of the invention to the representative embodiments shown and described herein. Rather, the scope and spirit of the invention is embodied by the appended claims.

While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Numerous variations, changes and substitutions will now occur to those skilled in the art without departing from the present invention. It is contemplated that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and thereby cover methods and structures within the scope of the claims and their equivalents.

All references cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent or patent application was specifically individually indicated to be incorporated by reference in its entirety for all purposes.

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SEQUENCE LISTING <110> THE CALIFORNIA INSTITUTE FOR BIOMEDICAL RESEARCH <120> COILED COIL IMMUNOGLOBULIN FUSION PROTEINS AND COMPOSITIONS THEREOF <130> 41135-712.601 <140> PCT/US2014/046419 <141> 2014-07-11 <150> 62/017,713 <151> 2014-06-26 <150> 61/925,904 <151> 2014-01-10 <150> 61/845,280 <151> 2013-07-11 <150> 61/845,287 <151> 2013-07-11 <160> 279 <170> PatentIn version 3.5 <210> 1 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca ggatgtgaat accgcggtcg catggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctattct gcatccttct tgtatagtgg ggtcccatca 180 aggttcagtg gcagtagatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagatttg caacttacta ctgtcaacag cattacacta cccctccgac gttcggccaa 300 ggtaccaagc ttgagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360 tctgatgagc agttgaaatc tggaactgcc tctgtcgtgt gcctgctgaa taacttctat 420 cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600 ctgtcctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642 <210> 2 <211> 81 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 2 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca g 81 <210> 3 <211> 552 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 3 accgcggtcg catggtatca gcagaaacca gggaaagccc ctaagctcct gatctattct 60 gcatccttct tgtatagtgg ggtcccatca aggttcagtg gcagtagatc tgggacagat 120 ttcactctca ccatcagcag tctgcaacct gaagattttg caacttacta ctgtcaacag 180 cattacacta cccctccgac gttcggccaa ggtaccaagc ttgagatcaa acgaactgtg 240 gctgcaccat ctgtcttcat cttcccgcca tctgatgagc agttgaaatc tggaactgcc 300 tctgtcgtgt gcctgctgaa taacttctat cccagagagg ccaaagtaca gtggaaggtg 360 gataacgccc tccaatcggg taactcccag gagagtgtca cagagcagga cagcaaggac 420 agcacctaca gcctcagcag caccctgacg ctgagcaaag cagactacga gaaacacaaa 480 gtctacgcct gcgaagtcac ccatcagggc ctgtcctcgc ccgtcacaaa gagcttcaac 540 aggggagagt gt 552 <210> 4 <211> 1353 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 4 gaagtgcagc tggtggaaag cggcggcggc ctggtgcagc cgggcggcag cctgcgcctg 60 agctgcgcgg cgagcggctt taacattaaa gatacctata ttcattgggt gcgccaggcg 120 ccgggcaaag gcctggaatg ggtggcgcgc atttatccga ccaacggcta tacccgctat 180 gcggatagcg tgaaaggccg ctttaccatt agcgcggata ccagcaaaaa caccgcgtat 240 ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcag ccgctggggc 300 ggcgatggct tttatgcgat ggattattgg ggccagggca ccctggtgac cgtgagcagc 360 gcgagcacca aaggcccgag cgtgtttccg ctggcgccga gcagcaaaag caccagcggc 420 ggcaccgcgg cgctgggctg cctggtgaaa gattattttc cggaaccggt gaccgtgagc 480 tggaacagcg gcgcgctgac cagcggcgtg catacctttc cggcggtgct gcagagcagc 540 ggcctgtata gcctgagcag cgtggtgacc gtgccgagca gcagcctggg cacccagacc 600 tatatttgca acgtgaacca taaaccgagc aacaccaaag tggataaaaa agtggaaccg 660 ccgaaaagct gcgataaaac ccatacctgc ccgccgtgcc cggcgccgga actgctgggc 720 ggcccgagcg tgtttctgtt tccgccgaaa ccgaaagata ccctgatgat tagccgcacc 780 ccggaagtga cctgcgtggt ggtggatgtg agccatgaag atccggaagt gaaatttaac 840 tggtatgtgg atggcgtgga agtgcataac gcgaaaacca aaccgcgcga agaacagtat 900 aacagcacct atcgcgtggt gagcgtgctg accgtgctgc atcaggattg gctgaacggc 960 aaagaatata aatgcaaagt gagcaacaaa gcgctgccgg cgccgattga aaaaaccatt 1020 agcaaagcga aaggccagcc gcgcgaaccg caggtgtata ccctgccgcc gagccgcgat 1080 gaactgacca aaaaccaggt gagcctgacc tgcctggtga aaggctttta tccgagcgat 1140 attgcggtgg aatgggaaag caacggccag ccggaaaaca actataaaac caccccgccg 1200 gtgctggata gcgatggcag cttttttctg tatagcaaac tgaccgtgga taaaagccgc 1260 tggcagcagg gcaacgtgtt tagctgcagc gtgatgcatg aagcgctgca taaccattat 1320 acccagaaaa gcctgagcct gagcccgggc aaa 1353 <210> 5 <211> 294 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 5 gaagtgcagc tggtggaaag cggcggcggc ctggtgcagc cgggcggcag cctgcgcctg 60 agctgcgcgg cgagcggctt taacattaaa gatacctata ttcattgggt gcgccaggcg 120 ccgggcaaag gcctggaatg ggtggcgcgc atttatccga ccaacggcta tacccgctat 180 gcggatagcg tgaaaggccg ctttaccatt agcgcggata ccagcaaaaa caccgcgtat 240 ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcag ccgc 294 <210> 6 <211> 1032 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 6 gattattggg gccagggcac cctggtgacc gtgagcagcg cgagcaccaa aggcccgagc 60 gtgtttccgc tggcgccgag cagcaaaagc accagcggcg gcaccgcggc gctgggctgc 120 ctggtgaaag attattttcc ggaaccggtg accgtgagct ggaacagcgg cgcgctgacc 180 agcggcgtgc atacctttcc ggcggtgctg cagagcagcg gcctgtatag cctgagcagc 240 gtggtgaccg tgccgagcag cagcctgggc acccagacct atatttgcaa cgtgaaccat 300 aaaccgagca acaccaaagt ggataaaaaa gtggaaccgc cgaaaagctg cgataaaacc 360 catacctgcc cgccgtgccc ggcgccggaa ctgctgggcg gcccgagcgt gtttctgttt 420 ccgccgaaac cgaaagatac cctgatgatt agccgcaccc cggaagtgac ctgcgtggtg 480 gtggatgtga gccatgaaga tccggaagtg aaatttaact ggtatgtgga tggcgtggaa 540 gtgcataacg cgaaaaccaa accgcgcgaa gaacagtata acagcaccta tcgcgtggtg 600 agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aagaatataa atgcaaagtg 660 agcaacaaag cgctgccggc gccgattgaa aaaaccatta gcaaagcgaa aggccagccg 720 cgcgaaccgc aggtgtatac cctgccgccg agccgcgatg aactgaccaa aaaccaggtg 780 agcctgacct gcctggtgaa aggcttttat ccgagcgata ttgcggtgga atgggaaagc 840 aacggccagc cggaaaacaa ctataaaacc accccgccgg tgctggatag cgatggcagc 900 ttttttctgt atagcaaact gaccgtggat aaaagccgct ggcagcaggg caacgtgttt 960 agctgcagcg tgatgcatga agcgctgcat aaccattata cccagaaaag cctgagcctg 1020 agcccgggca aa 1032 <210> 7 <211> 1350 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 7 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagatggggc 300 ggtgacggct tctatgccat ggactactgg ggccaaggaa ccctggtcac cgtctcctca 360 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgact gtgccctcta gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgaaccc 660 aaatcttgcg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1080 ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320 cagaagagcc tctccctgtc tccgggtaaa 1350 <210> 8 <211> 1347 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 8 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagatggggc 300 ggtgacggct tctatgccat ggactactgg ggccaaggaa ccctggtcac cgtctcctca 360 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgact gtgccctcta gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgaaccc 660 aaatcttgcg acaaaactca cacatgccca ccgtgcccag cacctccagt cgccggaccg 720 tcagtcttcc tcttccctcc aaaacccaag gacaccctca tgatctcccg gacccctgag 780 gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840 gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900 acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960 tacaagtgca aggtctccaa caaaggcctc ccaagctcca tcgagaaaac catctccaaa 1020 gccaaagggc agccccgaga accacaggtg tacaccctgc ctccatcccg ggatgagctg 1080 accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140 gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200 gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260 caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320 aagagcctct ccctgtctcc gggtaaa 1347 <210> 9 <211> 1341 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 9 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagatggggc 300 ggtgacggct tctatgccat ggactactgg ggccaaggaa ccctggtcac cgtctcctca 360 gccagcacta aaggtccatc tgtgttccct ctggctcctt gcagccggag cacctccgag 420 tccacagccg ctctgggatg tctggtgaaa gattacttcc ccgagcccgt caccgtgagc 480 tggaatagcg gagcactgac ctccggcgtc cacacattcc ccgccgtgct ccaaagctcc 540 ggcctgtaca gcctctcctc cgtggtcacc gtgcccagca gctctctggg cacaaagacc 600 tatacctgta acgtggatca caagcctagc aacaccaaag tggataagcg ggtggagagc 660 aagtacggcc ctccctgtcc cccttgcccc gctcctgagg ccgctggcgg accttccgtg 720 ttcctgtttc cccctaagcc caaggacacc ctcatgatta gccggacacc cgaagtgacc 780 tgcgtggtcg tggatgtgtc ccaggaggac cctgaagtgc aatttaactg gtacgtggac 840 ggcgtcgagg tgcacaacgc caagccaag cctcgggaag agcagttcaa cagcacctac 900 cgggtggtca gcgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtga gcaacaaggg cctgcccagc tccatcgaga agaccatcag caaggccaag 1020 ggccagccca gggaacccca ggtgtatacc ctgcccccta gccaggagga aatgaccaaa 1080 aaccaggtga gcctgacctg cctggtgaag ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca acggccagcc cgagaacaat tacaagacca cccctcctgt gctggacagc 1200 gacggctcct tctttctgta tagccggctg accgtggaca agagcaggtg gcaggagggc 1260 aacgtgttct cctgtagcgt gatgcacgag gccctgcaca accattacac ccagaagagc 1320 ttgagcctga gcctgggcaa a 1341 <210> 10 <211> 639 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 10 gacatccaga tgacccagtc cccctccacc ctgtccgcct ccgtgggcga ccgcgtgacc 60 atcacctgca agtgccagct gtccgtgggc tacatgcact ggtaccagca gaagcccggc 120 aaggccccca agctgctgat ctacgacacc tccaagctgg cctccggcgt gccctcccgc 180 ttctccggct ccggctccgg caccgagttc accctgacca tctcctccct gcagcccgac 240 gacttcgcca cctactactg cttccagggc tccggctacc ccttcacctt cggcggcggc 300 accaagctgg agatcaaacg aactgtggct gcaccatctg tcttcatctt cccgccatct 360 gatgagcagt tgaaatctgg aactgcctct gtcgtgtgcc tgctgaataa cttctatccc 420 agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480 agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540 agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600 tcctcgcccg tcacaaagag cttcaacagg ggagagtgt 639 <210> 11 <211> 297 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 11 caggtgaccc tgcgcgagtc cggccctgca ctggtgaagc ccacccagac cctgaccctg 60 acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgg 120 cagcctcccg gcaaggccct ggagtggctg gctgacatct ggtgggacga caagaaggac 180 tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240 gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgc 297 <210> 12 <211> 1048 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 12 gacgtgtggg gagccggtac caccgtgacc gtgtcttccg cctccaccaa gggcccatcg 60 gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 120 ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 180 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 240 gtggtgactg tgccctctag cagcttgggc acccagacct acatctgcaa cgtgaatcac 300 aagcccagca acaccaaggt ggacaagaaa gttgaaccca aatcttgcga caaaactcac 360 acatgcccac cgtgcccagc acctccagtc gccggaccgt cagtcttcct cttccctcca 420 aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 480 gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 540 aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 600 ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 660 aaaggcctcc caagctccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 720 ccacaggtgt acaccctgcc tccatcccgg gatgagctga ccaagaacca ggtcagcctg 780 acctgcctgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 840 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 900 ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 960 tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1020 ggtaaatgat aagtgctagc tggccaga 1048 <210> 13 <211> 1350 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 13 caggtgaccc tgcgcgagtc cggccccgcc ctggtgaagc ccacccagac cctgaccctg 60 acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgc 120 cagccccccg gcaaggccct ggagtggctg gccgacatct ggtgggacga caagaaggac 180 tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240 gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgctcc 300 atgatcacca actggtactt cgacgtgtgg ggcgccggca ccaccgtgac cgtgtcctcc 360 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgact gtgccctcta gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgaaccc 660 aaatcttgcg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1080 ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320 cagaagagcc tctccctgtc tccgggtaaa 1350 <210> 14 <211> 1347 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 14 caggtgaccc tgcgcgagtc cggccccgcc ctggtgaagc ccacccagac cctgaccctg 60 acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgc 120 cagccccccg gcaaggccct ggagtggctg gccgacatct ggtgggacga caagaaggac 180 tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240 gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgctcc 300 atgatcacca actggtactt cgacgtgtgg ggcgccggca ccaccgtgac cgtgtcctcc 360 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgact gtgccctcta gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgaaccc 660 aaatcttgcg acaaaactca cacatgccca ccgtgcccag cacctccagt cgccggaccg 720 tcagtcttcc tcttccctcc aaaacccaag gacaccctca tgatctcccg gacccctgag 780 gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840 gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900 acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960 tacaagtgca aggtctccaa caaaggcctc ccaagctcca tcgagaaaac catctccaaa 1020 gccaaagggc agccccgaga accacaggtg tacaccctgc ctccatcccg ggatgagctg 1080 accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140 gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200 gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260 caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320 aagagcctct ccctgtctcc gggtaaa 1347 <210> 15 <211> 1341 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 15 caggtgaccc tgcgcgagtc cggccccgcc ctggtgaagc ccacccagac cctgaccctg 60 acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgc 120 cagccccccg gcaaggccct ggagtggctg gccgacatct ggtgggacga caagaaggac 180 tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240 gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgctcc 300 atgatcacca actggtactt cgacgtgtgg ggcgccggca ccaccgtgac cgtgtcctcc 360 gccagcacta aaggtccatc tgtgttccct ctggctcctt gcagccggag cacctccgag 420 tccacagccg ctctgggatg tctggtgaaa gattacttcc ccgagcccgt caccgtgagc 480 tggaatagcg gagcactgac ctccggcgtc cacacattcc ccgccgtgct ccaaagctcc 540 ggcctgtaca gcctctcctc cgtggtcacc gtgcccagca gctctctggg cacaaagacc 600 tatacctgta acgtggatca caagcctagc aacaccaaag tggataagcg ggtggagagc 660 aagtacggcc ctccctgtcc cccttgcccc gctcctgagg ccgctggcgg accttccgtg 720 ttcctgtttc cccctaagcc caaggacacc ctcatgatta gccggacacc cgaagtgacc 780 tgcgtggtcg tggatgtgtc ccaggaggac cctgaagtgc aatttaactg gtacgtggac 840 ggcgtcgagg tgcacaacgc caagccaag cctcgggaag agcagttcaa cagcacctac 900 cgggtggtca gcgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtga gcaacaaggg cctgcccagc tccatcgaga agaccatcag caaggccaag 1020 ggccagccca gggaacccca ggtgtatacc ctgcccccta gccaggagga aatgaccaaa 1080 aaccaggtga gcctgacctg cctggtgaag ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca acggccagcc cgagaacaat tacaagacca cccctcctgt gctggacagc 1200 gacggctcct tctttctgta tagccggctg accgtggaca agagcaggtg gcaggagggc 1260 aacgtgttct cctgtagcgt gatgcacgag gccctgcaca accattacac ccagaagagc 1320 ttgagcctga gcctgggcaa a 1341 <210> 16 <211> 300 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 16 caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60 acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120 ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180 cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300 <210> 17 <211> 1035 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 17 tggcatgtgg atgtctgggg acagggcctg ctggtgacag tctctagtgc ttccacaact 60 gcaccaaagg tgtaccccct gtcaagctgc tgtggggaca aatcctctag taccgtgaca 120 ctgggatgcc tggtctcaag ctatatgccc gagcctgtga ctgtcacctg gaactcagga 180 gccctgaaaa gcggagtgca caccttccca gctgtgctgc agtcctctgg cctgtatagc 240 ctgagttcaa tggtgacagt ccccggcagt acttcagggc agaccttcac ctgtaatgtg 300 gcccatcctg ccagctccac caaagtggac aaagcagtgg aacccaaatc ttgcgacaaa 360 actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 420 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 480 gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 540 gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 600 gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 660 gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 720 ccccgagaac cacaggtgta caccctgccc ccatccggg atgagctgac caagaaccag 780 gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 840 agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 900 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 960 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1020 ctgtctccgg gtaaa 1035 <210> 18 <211> 648 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 18 caggccgtcc tgaaccagcc aagcagcgtc tccgggtctc tggggcagcg ggtctcaatc 60 acctgtagcg ggtcttcctc caatgtcggc aacggctacg tgtcttggta tcagctgatc 120 cctggcagtg ccccacgaac cctgatctac ggcgacacat ccagagcttc tggggtcccc 180 gatcggttct cagggagcag atccggaaac acagctactc tgaccatcag ctccctgcag 240 gctgaggacg aagcagatta tttctgcgca tctgccgagg actctagttc aaatgccgtg 300 tttggaagcg gcaccacact gacagtcctg gggcagccca agagtccccc ttcagtgact 360 ctgttcccac cctctaccga ggaactgaac ggaaacaagg ccacactggt gtgtctgatc 420 agcgactttt accctggatc cgtcactgtg gtctggaagg cagatggcag cacaattact 480 aggaacgtgg aaactacccg cgcctccaag cagtctaata gtaaatacgc cgccagctcc 540 tatctgagcc tgacctctag tgattggaag tccaaagggt catatagctg cgaagtgacc 600 catgaaggct caaccgtgac taagactgtg aaaccatccg agtgctcc 648 <210> 19 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 19 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 20 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 20 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 20 25 <210> 21 <211> 184 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 21 Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 1 5 10 15 Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe 20 25 30 Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 35 40 45 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr 50 55 60 Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val 65 70 75 80 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 85 90 95 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 100 105 110 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 115 120 125 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 130 135 140 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 145 150 155 160 Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr 165 170 175 Lys Ser Phe Asn Arg Gly Glu Cys 180 <210> 22 <211> 451 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 22 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 23 <211> 98 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 23 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg <210> 24 <211> 344 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 24 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 1 5 10 15 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 20 25 30 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 35 40 45 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 50 55 60 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 65 70 75 80 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 85 90 95 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 100 105 110 Pro Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 115 120 125 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Lys Pro 130 135 140 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 145 150 155 160 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 165 170 175 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 180 185 190 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 195 200 205 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 210 215 220 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 225 230 235 240 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 245 250 255 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 260 265 270 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 275 280 285 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 290 295 300 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 305 310 315 320 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 325 330 335 Ser Leu Ser Leu Ser Pro Gly Lys 340 <210> 25 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 25 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 26 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 26 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 27 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 27 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <210> 28 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 28 Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Cys Gln Leu Ser Val Gly Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp 65 70 75 80 Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser Gly Tyr Pro Phe Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 29 <211> 99 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 29 Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg <210> 30 <211> 342 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 30 Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 1 5 10 15 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 20 25 30 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 35 40 45 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 50 55 60 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 65 70 75 80 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 85 90 95 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 100 105 110 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 115 120 125 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Lys Pro Lys Asp 130 135 140 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 145 150 155 160 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 165 170 175 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 180 185 190 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 195 200 205 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 210 215 220 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 225 230 235 240 Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn 245 250 255 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 260 265 270 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 275 280 285 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 290 295 300 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 305 310 315 320 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 325 330 335 Ser Leu Ser Pro Gly Lys 340 <210> 31 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 31 Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Met Ile Thr Asn Trp Tyr Phe Asp Val Trp Gly Ala 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 32 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 32 Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Met Ile Thr Asn Trp Tyr Phe Asp Val Trp Gly Ala 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 33 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 33 Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Met Ile Thr Asn Trp Tyr Phe Asp Val Trp Gly Ala 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <210> 34 <211> 100 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 34 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln 100 <210> 35 <211> 345 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 35 Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser 1 5 10 15 Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly 20 25 30 Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Ser Tyr 35 40 45 Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser 50 55 60 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 65 70 75 80 Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe 85 90 95 Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala 100 105 110 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 115 120 125 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Lys 130 135 140 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 145 150 155 160 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 165 170 175 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 180 185 190 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 195 200 205 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 210 215 220 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 225 230 235 240 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu 245 250 255 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 260 265 270 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 275 280 285 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 290 295 300 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 305 310 315 320 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 325 330 335 Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 <210> 36 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 36 Gln Ala Val Leu Asn Gln Pro Ser Ser Val Ser Gly Ser Leu Gly Gln 1 5 10 15 Arg Val Ser Ile Thr Cys Ser Gly Ser Ser Ser Asn Val Gly Asn Gly 20 25 30 Tyr Val Ser Trp Tyr Gln Leu Ile Pro Gly Ser Ala Pro Arg Thr Leu 35 40 45 Ile Tyr Gly Asp Thr Ser Arg Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Arg Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ala Ser Ala Glu Asp Ser Ser 85 90 95 Ser Asn Ala Val Phe Gly Ser Gly Thr Thr Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Pro Pro Ser Val Thr Leu Phe Pro Ser Thr Glu Glu 115 120 125 Leu Asn Gly Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ser Val Thr Val Val Trp Lys Ala Asp Gly Ser Thr Ile Thr 145 150 155 160 Arg Asn Val Glu Thr Thr Arg Ala Ser Lys Gln Ser Asn Ser Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Ser Ser Asp Trp Lys Ser Lys 180 185 190 Gly Ser Tyr Ser Cys Glu Val Thr His Glu Gly Ser Thr Val Thr Lys 195 200 205 Thr Val Lys Pro Ser Glu Cys Ser 210 215 <210> 37 <211> 1269 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 37 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gggcggaagc ggagcaaagc tcgccgcact gaaagccaag 120 ctggccgctc tgaagggggg tggcggaagc gccccaccac gcctcatctg tgacagccga 180 gtcctggaga ggtacctctt ggaggccaag gaggccgaga atatcacgac gggctgtgct 240 gaacactgca gcttgaatga gaatatcact gtcccagaca ccaaagttaa tttctatgcc 300 tggaagagga tggaggtcgg gcagcaggcc gtagaagtct ggcagggcct ggccctgctg 360 tcggaagctg tcctgcgggg ccaggccctg ttggtcaact cttcccagcc gtgggagccc 420 ctgcagctgc atgtggataa agccgtcagt ggccttcgca gcctcaccac tctgcttcgg 480 gctctgggag cccagaagga agccatctcc cctccagatg cggcctcagc tgctccactc 540 cgaacaatca ctgctgacac tttccgcaaa ctcttccgag tctactccaa tttcctccgg 600 ggaaagctga agctgtacac aggggaggcc tgcaggacag gggacagagg cggaggtggg 660 agtgaactgg ccgcactgga agctgagctg gctgccctcg aagctggagg ctctggaacc 720 gcggtcgcat ggtatcagca gaaaccaggg aaagccccta agctcctgat ctattctgca 780 tccttcttgt atagtggggt cccatcaagg ttcagtggca gtagatctgg gacagatttc 840 actctcacca tcagcagtct gcaacctgaa gattttgcaa cttactactg tcaacagcat 900 tacactaccc ctccgacgtt cggccaaggt accaagcttg agatcaaacg aactgtggct 960 gcaccatctg tcttcatctt cccgccatct gatgagcagt tgaaatctgg aactgcctct 1020 gtcgtgtgcc tgctgaataa cttctatccc agagaggcca aagtacagtg gaaggtggat 1080 aacgccctcc aatcgggtaa ctcccaggag agtgtcacag agcaggacag caaggacagc 1140 acctacagcc tcagcagcac cctgacgctg agcaaagcag actacgagaa acacaaagtc 1200 tacgcctgcg aagtcaccca tcagggcctg tcctcgcccg tcacaaagag cttcaacagg 1260 ggagagtgt 1269 <210> 38 <211> 1983 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 38 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg aggcggtggc 360 tccacccccc ttggccctgc ccgatccctg ccccagagct tcctgctcaa gtgcttagag 420 caagtgagga aaatccaggc tgatggcgcc gagctgcagg agaggctgtg tgccgcccac 480 aagctgtgcc acccggagga gctgatgctg ctcaggcact ctctgggcat cccccaggct 540 cccctaagca gctgctccag ccagtccctg cagctgacga gctgcctgaa ccaactacac 600 ggcggcctct ttctctacca gggcctcctg caggccctgg cgggcatctc cccagagctg 660 gccccccacct tggacacact gcagctggac gtcactgact ttgccacgaa catctggctg 720 cagatggagg acctgggggc ggcccccgct gtgcagccca cccagggcgc catgccgacc 780 ttcacttcag ccttccaacg cagagcagga ggggtcctgg ttgcttccca gctgcatcgt 840 ttcctggagc tggcataccg tggcctgcgc taccttgctg agcccggcgg tggcggaagc 900 gaactggccg cactggaagc tgagctggct gccctcgaag ctggaggctc tggagactac 960 tggggccaag gaaccctggt caccgtctcc tcagcctcca ccaagggccc atcggtcttc 1020 cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 1080 aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 1140 gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 1200 actgtgccct ctagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 1260 agcaacacca aggtggacaa gaaagttgaa cccaaatctt gcgacaaaac tcacacatgc 1320 ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 1380 cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1440 agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1500 gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1560 accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 1620 gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1680 caggtgtaca ccctgccccc atcccgggat gagctgacca agaaccaggt cagcctgacc 1740 tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1800 ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1860 tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1920 gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1980 aaa 1983 <210> 39 <211> 1995 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 39 caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60 acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120 ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180 cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300 ggcggaagcg gagcaaagct cgccgcactg aaagccaagc tggccgctct gaagggaggc 360 ggtggctcca ccccccttgg ccctgcccga tccctgcccc agagcttcct gctcaagtgc 420 ttagagcaag tgaggaaaat ccaggctgat ggcgccgagc tgcaggagag gctgtgtgcc 480 gcccacaagc tgtgccaccc ggaggagctg atgctgctca ggcactctct gggcatcccc 540 caggctcccc taagcagctg ctccagccag tccctgcagc tgacgagctg cctgaaccaa 600 ctacacggcg gcctctttct ctaccagggc ctcctgcagg ccctggcggg catctcccca 660 gagctggccc ccaccttgga cacactgcag ctggacgtca ctgactttgc cacgaacatc 720 tggctgcaga tggaggacct gggggcggcc cccgctgtgc agcccaccca gggcgccatg 780 ccgaccttca cttcagcctt ccaacgcaga gcaggagggg tcctggttgc ttcccagctg 840 catcgtttcc tggagctggc ataccgtggc ctgcgctacc ttgctgagcc cggcggtggc 900 ggaagcgaac tggccgcact ggaagctgag ctggctgccc tcgaagctgg aggctctgga 960 tggcatgtgg atgtctgggg acagggcctg ctggtgacag tctctagtgc ttccacaact 1020 gcaccaaagg tgtaccccct gtcaagctgc tgtggggaca aatcctctag taccgtgaca 1080 ctgggatgcc tggtctcaag ctatatgccc gagcctgtga ctgtcacctg gaactcagga 1140 gccctgaaaa gcggagtgca caccttccca gctgtgctgc agtcctctgg cctgtatagc 1200 ctgagttcaa tggtgacagt ccccggcagt acttcagggc agaccttcac ctgtaatgtg 1260 gcccatcctg ccagctccac caaagtggac aaagcagtgg aacccaaatc ttgcgacaaa 1320 actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 1380 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 1440 gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 1500 gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 1560 gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 1620 gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1680 ccccgagaac cacaggtgta caccctgccc ccatccggg atgagctgac caagaaccag 1740 gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1800 agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1860 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1920 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1980 ctgtctccgg gtaaa 1995 <210> 40 <211> 1593 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 40 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaagtg cgggggtggc 360 ggaagcatcg aaggtcgtca cggagaagga acatttacca gcgacctcag caagcagatg 420 gaggaagagg ccgtgaggct gttcatcgag tggctgaaga acggcggacc ctcctctggc 480 gctccacccc ctagcggcgg aggtgggagt tgcgaactgg ccgcactgga agctgagctg 540 gctgccctcg aagctggagg ctctggagac tactggggcc aaggaaccct ggtcaccgtc 600 tcctcagcct ccaccaaggg cccatcggtc ttccccctgg caccctcctc caagagcacc 660 tctgggggca cagcggccct gggctgcctg gtcaaggact acttccccga accggtgacg 720 gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 780 tcctcaggac tctactccct cagcagcgtg gtgactgtgc cctctagcag cttgggcacc 840 cagacctaca tctgcaacgt gaatcacaag cccagcaaca ccaaggtgga caagaaagtt 900 gaacccaaat cttgcgacaa aactcacaca tgcccaccgt gcccagcacc tccagtcgcc 960 ggaccgtcag tcttcctctt ccctccaaaa cccaaggaca ccctcatgat ctccccggacc 1020 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 1080 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 1140 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1200 aaggagtaca agtgcaaggt ctccaacaaa ggcctcccaa gctccatcga gaaaaccatc 1260 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgcctcc atcccgggat 1320 gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1380 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1440 gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1500 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1560 acgcagaaga gcctctccct gtctccgggt aaa 1593 <210> 41 <211> 1563 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 41 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg aggcggtggc 360 tccatcaacg tgaagtgcag cctgccccag cagtgcatca agccctgcaa ggacgccggc 420 atgcggttcg gcaagtgcat gaacaagaag tgcaggtgct acagcggcgg tggcggaagc 480 gaactggccg cactggaagc tgagctggct gccctcgaag ctggaggctc tggagactac 540 tggggccaag gaaccctggt caccgtctcc tcagcctcca ccaagggccc atcggtcttc 600 cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 660 aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 720 gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 780 actgtgccct ctagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 840 agcaacacca aggtggacaa gaaagttgaa cccaaatctt gcgacaaaac tcacacatgc 900 ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 960 cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1020 agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1080 gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1140 accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 1200 gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1260 caggtgtaca ccctgccccc atcccgggat gagctgacca agaaccaggt cagcctgacc 1320 tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1380 ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1440 tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1500 gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1560 aaa 1563 <210> 42 <211> 1569 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 42 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg aggcggtggc 360 tccgccgctg caatctcctg cgtcggcagc cccgaatgtc ctcccaagtg ccgggctcag 420 ggatgcaaga acggcaagtg tatgaaccgg aagtgcaagt gctactattg cggcggtggc 480 ggaagcgaac tggccgcact ggaagctgag ctggctgccc tcgaagctgg aggctctgga 540 gactactggg gccaaggaac cctggtcacc gtctcctcag cctccaccaa gggcccatcg 600 gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 660 ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 720 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 780 gtggtgactg tgccctctag cagcttgggc acccagacct acatctgcaa cgtgaatcac 840 aagcccagca acaccaaggt ggacaagaaa gttgaaccca aatcttgcga caaaactcac 900 acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 960 ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 1020 gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1080 cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1140 gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 1200 aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1260 gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1320 ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1380 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1440 ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1500 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1560 ccgggtaaa 1569 <210> 43 <211> 1986 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 43 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg gggtggcgga 360 agcgccacac ctctgggccc cgcctcctcc ctgcctcaga gctttctgct caaatgtctg 420 gagcaggtgc ggaagatcca gggcgacggc gccgctctgc aagagaaact ggtcagcgaa 480 tgcgccacat ataagctgtg tcaccccgag gaactggtcc tcttgggcca cagcctgggc 540 atcccctggg cccctctcag ctcctgcccc tcccaagctc tccaactggc tggatgtctg 600 tcccaactgc actccggcct cttcctgtac cagggactcc tccaggctct cgaagggatc 660 agccccgaac tgggccccac actggacacc ttgcaactcg atgtggccga tttcgccaca 720 accatctggc agcagatgga agaactcgga atggctcctg ctctccagcc cacacaggga 780 gctatgcctg ctttcgcctc tgctttccag cggagagctg gtggtgtgct cgtcgcatcc 840 cacctccaga gcttcttgga ggtgtcctat cgggtgctcc ggcatctggc ccaacccggc 900 ggaggtggga gtgaactggc cgcactggaa gctgagctgg ctgccctcga agctggaggc 960 tctggagact actggggcca aggaaccctg gtcaccgtct cctcagccag cactaaaggt 1020 ccatctgtgt tccctctggc tccttgcagc cggagcacct ccgagtccac agccgctctg 1080 ggatgtctgg tgaaagatta cttccccgag cccgtcaccg tgagctggaa tagcggagca 1140 ctgacctccg gcgtccacac attccccgcc gtgctccaaa gctccggcct gtacagcctc 1200 tcctccgtgg tcaccgtgcc cagcagctct ctgggcacaa agacctatac ctgtaacgtg 1260 gatcacaagc ctagcaacac caaagtggat aagcgggtgg agagcaagta cggccctccc 1320 tgtccccctt gccccgctcc tgaggccgct ggcggacctt ccgtgttcct gtttccccct 1380 aagcccaagg acaccctcat gattagccgg acacccgaag tgacctgcgt ggtcgtggat 1440 gtgtcccagg aggaccctga agtgcaattt aactggtacg tggacggcgt cgaggtgcac 1500 aacgccaaga ccaagcctcg ggaagagcag ttcaacagca cctaccgggt ggtcagcgtg 1560 ctgacagtgc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtgagcaac 1620 aagggcctgc ccagctccat cgagaagacc atcagcaagg ccaagggcca gcccagggaa 1680 ccccaggtgt ataccctgcc ccctagccag gaggaaatga ccaaaaacca ggtgagcctg 1740 acctgcctgg tgaagggctt ctaccccagc gacatcgccg tggagtggga gagcaacggc 1800 cagcccgaga acaattacaa gaccacccct cctgtgctgg acagcgacgg ctccttcttt 1860 ctgtatagcc ggctgaccgt ggacaagagc aggtggcagg agggcaacgt gttctcctgt 1920 agcgtgatgc acgaggccct gcacaaccat tacacccaga agagcttgag cctgagcctg 1980 ggcaaa 1986 <210> 44 <211> 2025 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 44 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg gggtggcgga 360 agcttcccaa ccattccctt atccaggctt tttgacaacg ctatgctccg cgcccatcgt 420 ctgcaccagc tggcctttga cacctaccag gagtttgaag aagcctatat cccaaaggaa 480 cagaagtatt cattcctgca gaacccccag acctccctct gtttctcaga gtctattccg 540 acaccctcca acagggagga aacacaacag aaatccaacc tagagctgct ccgcatctcc 600 ctgctgctca tccagtcgtg gctggagccc gtgcagttcc tcaggagtgt cttcgccaac 660 agcctggtgt acggcgcctc tgacagcaac gtctatgacc tcctaaagga cctagaggaa 720 ggcatccaaa cgctgatggg gaggctggaa gatggcagcc cccggactgg gcagatcttc 780 aagcagacct acagcaagtt cgacacaaac tcacacaacg atgacgcact actcaagaac 840 tacgggctgc tctactgctt caggaaggac atggacaagg tcgagacatt cctgcgcatc 900 gtgcagtgcc gctctgtgga gggcagctgt ggcttcggcg gaggtgggag tgaactggcc 960 gcactggaag ctgagctggc tgccctcgaa gctggaggct ctggagacta ctggggccaa 1020 ggaaccctgg tcaccgtctc ctcagccagc actaaaggtc catctgtgtt ccctctggct 1080 ccttgcagcc ggagcacctc cgagtccaca gccgctctgg gatgtctggt gaaagattac 1140 ttccccgagc ccgtcaccgt gagctggaat agcggagcac tgacctccgg cgtccacaca 1200 ttccccgccg tgctccaaag ctccggcctg tacagcctct cctccgtggt caccgtgccc 1260 agcagctctc tgggcacaaa gacctatacc tgtaacgtgg atcacaagcc tagcaacacc 1320 aaagtggata agcgggtgga gagcaagtac ggccctccct gtcccccttg ccccgctcct 1380 gaggccgctg gcggaccttc cgtgttcctg tttcccccta agcccaagga caccctcatg 1440 attagccgga cacccgaagt gacctgcgtg gtcgtggatg tgtcccagga ggaccctgaa 1500 gtgcaattta actggtacgt ggacggcgtc gaggtgcaca acgccaagac caagcctcgg 1560 gaagagcagt tcaacagcac ctaccgggtg gtcagcgtgc tgacagtgct gcaccaggac 1620 tggctgaacg gcaaggagta caagtgcaag gtgagcaaca agggcctgcc cagctccatc 1680 gagaagacca tcagcaaggc caagggccag cccagggaac cccaggtgta taccctgccc 1740 cctagccagg aggaaatgac caaaaaccag gtgagcctga cctgcctggt gaagggcttc 1800 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caattacaag 1860 accacccctc ctgtgctgga cagcgacggc tccttctttc tgtatagccg gctgaccgtg 1920 gacaagagca ggtggcagga gggcaacgtg ttctcctgta gcgtgatgca cgaggccctg 1980 cacaaccatt accaccagaa gagcttgagc ctgagcctgg gcaaa 2025 <210> 45 <211> 2058 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 45 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatcctg gcggaagcgg agcaaagctc 180 gccgcactga aagccaagct ggccgctctg aagggtggtg gcggaagctt cccaaccatt 240 cccttatcca ggctttttga caacgctatg ctccgcgccc atcgtctgca ccagctggcc 300 tttgacacct accaggagtt tgaagaagcc tatatcccaa aggaacagaa gtattcattc 360 ctgcagaacc cccagacctc cctctgtttc tcagagtcta ttccgacacc ctccaacagg 420 gaggaaacac aacagaaatc caacctagag ctgctccgca tctccctgct gctcatccag 480 tcgtggctgg agcccgtgca gttcctcagg agtgtcttcg ccaacagcct ggtgtacggc 540 gcctctgaca gcaacgtcta tgacctccta aaggacctag aggaaggcat ccaaacgctg 600 atggggaggc tggaagatgg cagcccccgg actgggcaga tcttcaagca gacctacagc 660 aagttcgaca caaactcaca caacgatgac gcactactca agaactacgg gctgctctac 720 tgcttcagga aggacatgga caaggtcgag acattcctgc gcatcgtgca gtgccgctct 780 gtggagggca gctgtggctt cggcggaggt gggagtgaac tggccgcact ggaagctgag 840 ctggctgccc tcgaagctgg aggctctgga ggttacacac gctacgcaga ctccgtgaag 900 ggccgattca ccatctccgc agacacttcc aagaacacgg cgtatcttca aatgaacagc 960 ctgagagccg aggacacggc cgtgtattac tgttcgagat ggggcggtga cggcttctat 1020 gccatggact actggggcca aggaaccctg gtcaccgtct cctcagcctc caccaagggc 1080 ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 1140 ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 1200 ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 1260 agcagcgtgg tgactgtgcc ctctagcagc ttgggcaccc agacctacat ctgcaacgtg 1320 aatcacaagc ccagcaacac caaggtggac aagaaagttg aacccaaatc ttgcgacaaa 1380 actcacacat gcccaccgtg cccagcacct ccagtcgccg gaccgtcagt cttcctcttc 1440 cctccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 1500 gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 1560 gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc 1620 agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1680 tccaacaaag gcctcccaag ctccatcgag aaaaccatct ccaaagccaa agggcagccc 1740 cgagaaccac aggtgtacac cctgcctcca tcccgggatg agctgaccaa gaaccaggtc 1800 agcctgacct gcctggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1860 aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1920 ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1980 tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 2040 tctccgggta aatgataa 2058 <210> 46 <211> 2028 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 46 caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60 acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120 ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180 cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcggcgg aagcggagca 300 aagctcgccg cactgaaagc caagctggcc gctctgaagg ggggtggcgg aagcttccca 360 accattccct tatccaggct ttttgacaac gctatgctcc gcgcccatcg tctgcaccag 420 ctggcctttg acacctacca ggagtttgaa gaagcctata tcccaaagga acagaagtat 480 tcattcctgc agaaccccca gacctccctc tgtttctcag agtctattcc gacaccctcc 540 aacagggagg aaacacaaca gaaatccaac ctagagctgc tccgcatctc cctgctgctc 600 atccagtcgt ggctggagcc cgtgcagttc ctcaggagtg tcttcgccaa cagcctggtg 660 tacggcgcct ctgacagcaa cgtctatgac ctcctaaagg acctagagga aggcatccaa 720 acgctgatgg ggaggctgga agatggcagc ccccggactg ggcagatctt caagcagacc 780 tacagcaagt tcgacacaaa ctcacacaac gatgacgcac tactcaagaa ctacgggctg 840 ctctactgct tcaggaagga catggacaag gtcgagacat tcctgcgcat cgtgcagtgc 900 cgctctgtgg agggcagctg tggcttcggc ggaggtggga gtgaactggc cgcactggaa 960 gctgagctgg ctgccctcga agctggaggc tctggacatg tggatgtctg gggacagggc 1020 ctgctggtga cagtctctag tgcttccaca actgcaccaa aggtgtaccc cctgtcaagc 1080 tgctgtgggg acaaatcctc tagtaccgtg acactgggat gcctggtctc aagctatatg 1140 cccgagcctg tgactgtcac ctggaactca ggagccctga aaagcggagt gcacaccttc 1200 ccagctgtgc tgcagtcctc tggcctgtat agcctgagtt caatggtgac agtccccggc 1260 agtacttcag ggcagacctt cacctgtaat gtggcccatc ctgccagctc caccaaagtg 1320 gacaaagcag tggaacccaa atcttgcgac aaaactcaca catgcccacc gtgcccagca 1380 cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 1440 atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 1500 gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1560 cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1620 gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagcccccc 1680 atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1740 cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1800 ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1860 aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1920 gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1980 ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 2028 <210> 47 <211> 1896 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 47 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg gggtggcgga 360 agcgttccaa ttcaaaaggt tcaagatgat accaaaactc tgattaaaac tattgtcacg 420 cgtataaacg acatcagcca tacccagtcg gttagctcaa agcaaaaagt taccggtttg 480 gactttattc cgggactgca cccgatcctg acccttagta aaatggacca gacactggcc 540 gtctaccagc aaatcctgac atcgatgcca tccagaaatg tgatacaaat tagcaacgat 600 ttggaaaacc ttcgcgatct gctgcacgtg ctggccttca gtaagtcctg tcatctgccg 660 tgggcgtcgg gactggagac tcttgactcg ctgggtggag tgttagaggc ctctggctat 720 tctactgaag tcgttgcgct gtcacgcctc caggggagcc tgcaggacat gctgtggcag 780 ctggacctgt cacctggctg cggcggaggt gggagtgaac tggccgcact ggaagctgag 840 ctggctgccc tcgaagctgg aggctctgga gactactggg gccaaggaac cctggtcacc 900 gtctcctcag cctccaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 960 acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 1020 acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 1080 cagtcctcag gactctactc cctcagcagc gtggtgactg tgccctctag cagcttgggc 1140 acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaaa 1200 gttgaaccca aatcttgcga caaaactcac acatgcccac cgtgcccagc acctccagtc 1260 gccggaccgt cagtcttcct cttccctcca aaacccaagg acaccctcat gatctcccgg 1320 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 1380 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1440 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1500 ggcaaggagt acaagtgcaa ggtctccaac aaaggcctcc caagctccat cgagaaaacc 1560 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc tccatcccgg 1620 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1680 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1740 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1800 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1860 tacaccgcaga agagcctctc cctgtctccg ggtaaa 1896 <210> 48 <211> 1911 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 48 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt attggcggaa gcggagcaaa gctcgccgca 180 ctgaaagcca agctggccgc tctgaagggg ggtggcggaa gcgttccaat tcaaaaggtt 240 caagatgata ccaaaactct gattaaaact attgtcacgc gtataaacga catctcacat 300 acccagtcgg ttagctcaaa gcaaaaagtt accggtttgg actttattcc gggactgcac 360 ccgatcctga cccttagtaa aatggaccag acactggccg tctaccagca aatcctgaca 420 tcgatgccat ccagaaatgt gatacaaatt agcaacgatt tggaaaacct tcgcgatctg 480 ctgcacgtgc tggccttcag taagtcctgt catctgccgt gggcgtcggg actggagact 540 cttgactcgc tgggtggagt gttagaggcc tctggctatt ctactgaagt cgttgcgctg 600 tcacgcctcc aggggagcct gcaggacatg ctgtggcagc tggacctgtc acctggctgc 660 ggcggaggtg ggagtgaact ggccgcactg gaagctgagc tggctgccct cgaagctgga 720 ggctctggaa cacgctacgc agactccgtg aagggccgat tcaccatctc cgcagacact 780 tccaagaaca cggcgtatct tcaaatgaac agcctgagag ccgaggacac ggccgtgtat 840 tactgttcga gatggggcgg tgacggcttc tatgccatgg actactgggg ccaaggaacc 900 ctggtcaccg tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 960 tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 1020 gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 1080 gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgactgt gccctctagc 1140 agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 1200 gacaagaaag ttgaacccaa atcttgcgac aaaactcaca catgcccacc gtgcccagca 1260 cctccagtcg ccggaccgtc agtcttcctc ttccctccaa aacccaagga caccctcatg 1320 atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 1380 gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1440 gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1500 tggctgaatg gcaaggagta caagtgcaag gtctccaaca aaggcctccc aagctccatc 1560 gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgcct 1620 ccatccccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1680 tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1740 accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1800 gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1860 cacaaccact acaccgcagaa gagcctctcc ctgtctccgg gtaaatgata a 1911 <210> 49 <211> 1209 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 49 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca ggatgtgaat accgcggtcg catggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctattct gcatccttct tgtatagtgg ggtcccatca 180 aggttcagtg gcagtagatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag cattacggcg gaagcggagc aaagctcgcc 300 gcactgaaag ccaagctggc cgctctgaag gggggtggcg gaagcgttcc aattcaaaag 360 gttcaagatg ataccaaaac tctgattaaa actattgtca cgcgtataaa cgacatctca 420 catacccagt cggttagctc aaagcaaaaa gttaccggtt tggactttat tccgggactg 480 cacccgatcc tgacccttag taaaatggac cagacactgg ccgtctacca gcaaatcctg 540 acatcgatgc catccagaaa tgtgatacaa attagcaacg atttggaaaa ccttcgcgat 600 ctgctgcacg tgctggcctt cagtaagtcc tgtcatctgc cgtgggcgtc gggactggag 660 actcttgact cgctgggtgg agtgttagag gcctctggct attctactga agtcgttgcg 720 ctgtcacgcc tccaggggag cctgcaggac atgctgtggc agctggacct gtcacctggc 780 tgcggcggag gtgggagtga actggccgca ctggaagctg agctggctgc cctcgaagct 840 ggaggctctg gaccgacgtt cggccaaggt accaagcttg agatcaaacg aactgtggct 900 gcaccatctg tcttcatctt cccgccatct gatgagcagt tgaaatctgg aactgcctct 960 gtcgtgtgcc tgctgaataa cttctatccc agagaggcca aagtacagtg gaaggtggat 1020 aacgccctcc aatcgggtaa ctcccaggag agtgtcacag agcaggacag caaggacagc 1080 acctacagcc tcagcagcac cctgacgctg agcaaagcag actacgagaa acacaaagtc 1140 tacgcctgcg aagtcaccca tcagggcctg tcctcgcccg tcacaaagag cttcaacagg 1200 ggagagtgt 1209 <210> 50 <211> 1947 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 50 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg tggtggcgga 360 agctgtgatc tgcctcaaac ccacagcctg ggtagcagga ggaccttgat gctcctggca 420 cagatgagga gaatctctct tttctcctgc ttgaaggaca gacatgactt tggatttccc 480 caggaggagt ttggcaacca gttccaaaag gctgaaacca tccctgtcct ccatgagatg 540 atccagcaga tcttcaatct cttcagcaca aaggactcat ctgctgcttg ggatgagacc 600 ctcctagaca aattctacac tgaactctac cagcagctga atgacctgga agcctgtgtg 660 atacagggg tgggggtgac agagactccc ctgatgaagg aggactccat tctggctgtg 720 aggaaatact tccaaagaat cactctctat ctgaaagaga agaaatacag cccttgtgcc 780 tgggaggttg tcagagcaga aatcatgaga tctttttctt tgtcaacaaa cttgcaagaa 840 agtttaagaa gtaaggaagg cggaggtggg agtgaactgg ccgcactgga agctgagctg 900 gctgccctcg aagctggagg ctctggagac tactggggcc aaggaaccct ggtcaccgtc 960 tcctcagcca gcactaaagg tccatctgtg ttccctctgg ctccttgcag ccggagcacc 1020 tccgagtcca cagccgctct gggatgtctg gtgaaagatt acttccccga gcccgtcacc 1080 gtgagctgga atagcggagc actgacctcc ggcgtccaca cattccccgc cgtgctccaa 1140 agctccggcc tgtacagcct ctcctccgtg gtcaccgtgc ccagcagctc tctgggcaca 1200 aagacctata cctgtaacgt ggatcacaag cctagcaaca ccaaagtgga taagcgggtg 1260 gagagcaagt acggccctcc ctgtccccct tgccccgctc ctgaggccgc tggcggacct 1320 tccgtgttcc tgtttccccc taagcccaag gacaccctca tgattagccg gacacccgaa 1380 gtgacctgcg tggtcgtgga tgtgtcccag gaggaccctg aagtgcaatt taactggtac 1440 gtggacggcg tcgaggtgca caacgccaag accaagcctc gggaagagca gttcaacagc 1500 acctaccggg tggtcagcgt gctgacagtg ctgcaccagg actggctgaa cggcaaggag 1560 tacaagtgca aggtgagcaa caagggcctg cccagctcca tcgagaagac catcagcaag 1620 gccaagggcc agcccaggga accccaggtg tataccctgc cccctagcca ggaggaaatg 1680 accaaaaacc aggtgagcct gacctgcctg gtgaagggct tctaccccag cgacatcgcc 1740 gtggagtggg agagcaacgg ccagcccgag aacaattaca agaccacccc tcctgtgctg 1800 gacagcgacg gctccttctt tctgtatagc cggctgaccg tggacaagag caggtggcag 1860 gagggcaacg tgttctcctg tagcgtgatg cacgaggccc tgcacaacca ttacacccag 1920 aagagcttga gcctgagcct gggcaaa 1947 <210> 51 <211> 1962 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 51 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg tggtggcgga 360 agcatgagct acaacttgct tggattccta caaagaagca gcaattttca gtgtcagaag 420 ctcctgtggc aattgaatgg gaggcttgaa tactgcctca aggacaggat gaactttgac 480 atccctgagg agattaagca gctgcagcag ttccagaagg aggacgccgc attgaccatc 540 tatgagatgc tccagaacat ctttgctatt ttcagacaag attcatctag cactggctgg 600 aatgagacta ttgttgagaa cctcctggct aatgtctatc atcagataaa ccatctgaag 660 acagtcctgg aagaaaaact ggagaaagaa gatttcacca ggggaaaact catgagcagt 720 ctgcacctga aaagatatta tgggaggatt ctgcattacc tgaaggccaa ggagtacagt 780 cactgtgcct ggaccatagt cagagtggaa atcctaagga acttttactt cattaacaga 840 cttacaggtt acctccgaaa cggcggaggt gggagtgaac tggccgcact ggaagctgag 900 ctggctgccc tcgaagctgg aggctctgga gactactggg gccaaggaac cctggtcacc 960 gtctcctcag cctccaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 1020 acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 1080 acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 1140 cagtcctcag gactctactc cctcagcagc gtggtgactg tgccctctag cagcttgggc 1200 acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaaa 1260 gttgaaccca aatcttgcga caaaactcac acatgcccac cgtgcccagc acctccagtc 1320 gccggaccgt cagtcttcct cttccctcca aaacccaagg acaccctcat gatctcccgg 1380 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 1440 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1500 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1560 ggcaaggagt acaagtgcaa ggtctccaac aaaggcctcc caagctccat cgagaaaacc 1620 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc tccatcccgg 1680 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1740 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1800 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1860 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1920 tacaccgcaga agagcctctc cctgtctccg ggtaaatgat aa 1962 <210> 52 <211> 1953 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 52 caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60 acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120 ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180 cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcggcgg aagcggagca 300 aagctcgccg cactgaaagc caagctggcc gctctgaagg ggggtggcgg aagcatgagc 360 tacaacttgc ttggattcct acaaagaagc agcaattttc agtgtcagaa gctcctgtgg 420 caattgaatg ggaggcttga atactgcctc aaggacagga tgaactttga catccctgag 480 gagattaagc agctgcagca gttccagaag gaggacgccg cattgaccat ctatgagatg 540 ctccagaaca tctttgctat tttcagacaa gattcatcta gcactggctg gaatgagact 600 attgttgaga acctcctggc taatgtctat catcagataa accatctgaa gacagtcctg 660 gaagaaaaac tggagaaaga agatttcacc aggggaaaac tcatgagcag tctgcacctg 720 aaaagatatt atgggaggat tctgcattac ctgaaggcca aggagtacag tcactgtgcc 780 tggaccatag tcagagtgga aatcctaagg aacttttact tcattaacag acttacaggt 840 tacctccgaa acggcggagg tgggagtgaa ctggccgcac tggaagctga gctggctgcc 900 ctcgaagctg gaggctctgg acatgtggat gtctggggac agggcctgct ggtgacagtc 960 tctagtgctt ccacaactgc accaaaggtg taccccctgt caagctgctg tggggacaaa 1020 tcctctagta ccgtgacact gggatgcctg gtctcaagct atatgcccga gcctgtgact 1080 gtcacctgga actcaggagc cctgaaaagc ggagtgcaca ccttcccagc tgtgctgcag 1140 tcctctggcc tgtatagcct gagttcaatg gtgacagtcc ccggcagtac ttcagggcag 1200 accttcacct gtaatgtggc ccatcctgcc agctccacca aagtggacaa agcagtggaa 1260 cccaaatctt gcgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 1320 ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctccccggacc 1380 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 1440 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 1500 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1560 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1620 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggat 1680 gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1740 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1800 gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1860 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1920 acgcagaaga gcctctccct gtctccgggt aaa 1953 <210> 53 <211> 1566 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 53 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaagtg cgggggtggc 360 ggaagcatcg aaggtcgtca cgctgaggga acattcactt ccgatgtgtc ctcctacctg 420 gagggccagg ctgccaaaga gttcatcgct tggctcgtca agggcagggg cggaggtggg 480 agttgcgaac tggccgcact ggaagctgag ctggctgccc tcgaagctgg aggctctgga 540 gactactggg gccaaggaac cctggtcacc gtctcctcag cctccaccaa gggcccatcg 600 gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 660 ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 720 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 780 gtggtgactg tgccctctag cagcttgggc acccagacct acatctgcaa cgtgaatcac 840 aagcccagca acaccaaggt ggacaagaaa gttgaaccca aatcttgcga caaaactcac 900 acatgcccac cgtgcccagc acctccagtc gccggaccgt cagtcttcct cttccctcca 960 aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 1020 gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1080 aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1140 ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 1200 aaaggcctcc caagctccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1260 ccacaggtgt acaccctgcc tccatcccgg gatgagctga ccaagaacca ggtcagcctg 1320 acctgcctgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 1380 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1440 ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1500 tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1560 ggtaaa 1566 <210> 54 <211> 1629 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 54 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg gggtggcgga 360 agcgcgcaag agccagtcaa aggtccagtc tccactaagc ctggctcctg ccccattatc 420 ttgatccggt gcgccatgtt gaatccccct aaccgctgct tgaaagatac tgactgccca 480 ggaatcaaga agtgctgtga aggctcttgc gggatggcct gtttcgttcc ccagggcgga 540 ggtgggagtg aactggccgc actggaagct gagctggctg ccctcgaagc tggaggctct 600 ggagactact ggggccaagg aaccctggtc accgtctcct cagcctccac caagggccca 660 tcggtcttcc ccctggcacc ctcctccaag agcacctctg ggggcacagc ggccctgggc 720 tgcctggtca aggactactt ccccgaaccg gtgacggtgt cgtggaactc aggcgccctg 780 accagcggcg tgcacacctt cccggctgtc ctacagtcct caggactcta ctccctcagc 840 agcgtggtga ctgtgccctc tagcagcttg ggcacccaga cctacatctg caacgtgaat 900 cacaagccca gcaacaccaa ggtggacaag aaagttgaac ccaaatcttg cgacaaaact 960 cacacatgcc caccgtgccc agcacctcca gtcgccggac cgtcagtctt cctcttccct 1020 ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 1080 gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1140 cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1200 gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 1260 aacaaaggcc tcccaagctc catcgagaaa accatctcca aagccaaagg gcagccccga 1320 gaaccacagg tgtacaccct gcctccatcc cgggatgagc tgaccaagaa ccaggtcagc 1380 ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1440 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1500 ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1560 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1620 ccgggtaaa 1629 <210> 55 <211> 1740 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 55 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg aggtggcggg 360 agcgactctt ggatggaaga agttatcaaa ctgtgcggtc gtgaactggt tcgtgctcag 420 atcgctatct gcggtatgtc tacctggtct aaacgtgagg cagaggacct gcaggtgggg 480 caggtggagc tgggcggggg ccctggtgca ggcagcctgc agcccttggc cctggagggg 540 tccctgcaga agcgtcgtaa aaaacgtcag ctgtactctg ctctggctaa caaatgctgc 600 cacgttggtt gcaccaaacg ttctctggct cgtttctgcg gcggaggtgg gagtgaactg 660 gccgcactgg aagctgagct ggctgccctc gaagctggag gctctggaga ctactggggc 720 caaggaaccc tggtcaccgt ctcctcagcc tccaccaagg gcccatcggt cttccccctg 780 gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 840 tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 900 accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgactgtg 960 ccctctagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 1020 accaaggtgg acaagaaagt tgaacccaaa tcttgcgaca aaactcacac atgcccaccg 1080 tgcccagcac ctccagtcgc cggaccgtca gtcttcctct tccctccaaa acccaaggac 1140 accctcatga tctcccggac ccctgaggtc acatgcgtgg tggtggacgt gagccacgaa 1200 gaccctgagg tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca 1260 aagccgcggg aggagcagta caacagcacg taccgtgtgg tcagcgtcct caccgtcctg 1320 caccaggact ggctgaatgg caaggagtac aagtgcaagg tctccaacaa aggcctccca 1380 agctccatcg agaaaaccat ctccaaagcc aaagggcagc cccgagaacc acaggtgtac 1440 accctgcctc catcccggga tgagctgacc aagaaccagg tcagcctgac ctgcctggtc 1500 aaaggcttct atcccagcga catcgccgtg gagtgggaga gcaatgggca gccggagaac 1560 aactacaaga ccacgcctcc cgtgctggac tccgacggct ccttcttcct ctacagcaag 1620 ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcat 1680 gaggctctgc acaaccacta cacgcagaag agcctctccc tgtctccggg taaatgataa 1740 <210> 56 <211> 1626 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 56 gaagtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gggcggaagc 300 ggagcaaagc tcgccgcact gaaagccaag ctggccgctc tgaagggggg tggcggaagc 360 ctgaaatgtt accaacatgg taaagttgtg acttgtcatc gagatatgaa gttttgctat 420 cataacactg gcatgccttt tcgaaatctc aagctcatcc tacagggatg ttcttcttcg 480 tgcagtgaaa cagaaaacaa taagtgttgc tcaacagaca gatgcaacaa aggcggaggt 540 gggagtgaac tggccgcact ggaagctgag ctggctgccc tcgaagctgg aggctctgga 600 tggggccaag gaaccctggt caccgtctcc tcagcctcca ccaagggccc atcggtcttc 660 cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 720 aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 780 gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 840 actgtgccct ctagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 900 agcaacacca aggtggacaa gaaagttgaa cccaaatctt gcgacaaaac tcacacatgc 960 ccaccgtgcc cagcacctcc agtcgccgga ccgtcagtct tcctcttccc tccaaaaccc 1020 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 1080 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 1140 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1200 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaaggc 1260 ctcccaagct ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1320 gtgtacaccc tgcctccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 1380 ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1440 gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1500 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1560 atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1620 tgataa 1626 <210> 57 <211> 1566 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 57 caggtgaccc tgcgcgagtc cggccctgca ctggtgaagc ccacccagac cctgaccctg 60 acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgg 120 cagcctcccg gcaaggccct ggagtggctg gctgacatct ggtgggacga caagaaggac 180 tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240 gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgctct 300 tctgaaacta agaaaggggg tggcggaagc ctgaaatgtt accaacatgg taaagttgtg 360 acttgtcatc gagatatgaa gttttgctat cataacactg gcatgccttt tcgaaatctc 420 aagctcatcc tacagggatg ttcttcttcg tgcagtgaaa cagaaaacaa taagtgttgc 480 tcaacagaca gatgcaacaa aggcggaggt gggagttaca attatgaata ctttgacgtg 540 tggggagccg gtaccaccgt gaccgtgtct tccgcctcca ccaagggccc atcggtcttc 600 cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 660 aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 720 gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 780 actgtgccct ctagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 840 agcaacacca aggtggacaa gaaagttgaa cccaaatctt gcgacaaaac tcacacatgc 900 ccaccgtgcc cagcacctcc agtcgccgga ccgtcagtct tcctcttccc tccaaaaccc 960 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 1020 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 1080 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1140 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaaggc 1200 ctcccaagct ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1260 gtgtacaccc tgcctccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 1320 ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1380 gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1440 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1500 atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1560 tgataa 1566 <210> 58 <211> 1660 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 58 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg aggtggcggg 360 agcgactctt ggatggaaga agttatcaaa ctgtgcggtc gtgaactggt tcgtgctcag 420 atcgctatct gcggtatgtc tacctggtct aaacgttctc tgtctcagga aatcgagggc 480 cgtaaaaaac gtcagctgta ctctgctctg gctaacaaat gctgccacgt tggttgcacc 540 aaacgttctc tggctcgttt ctgcggcgga ggtgggagtg aactggccgc actggaagct 600 gagctggctg ccctcgaagc tggaggctct ggagactact ggggccaagg aaccctggtc 660 accgtctcct cagcctccac caagggccca tcggtcttcc ccctggcacc ctcctccaag 720 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 780 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 840 ctacagtcct caggactcta ctccctcagc agcgtggtga ctgtgccctc tagcagcttg 900 ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 960 aaagttgaac ccaaatcttg cgacaaaact cacacatgcc caccgtgccc agcacctcca 1020 gtcgccggac cgtcagtctt cctcttccct ccaaaaccca aggacaccct catgatctcc 1080 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 1140 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1200 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1260 aatggcaagg agtacaagtg caaggtctcc aacaaaggcc tcccaagctc catcgagaaa 1320 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcctccatcc 1380 cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1440 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1500 cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1560 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1620 cactacacgc agaagagcct ctccctgtct ccgggtaaat 1660 <210> 59 <211> 1686 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 59 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg aggtggcggg 360 agcgactctt ggatggaaga agttatcaaa ctgtgcggtc gtgaactggt tcgtgctcag 420 atcgctatct gcggtatgtc tacctggtct aaacgttctc tgtctcagga agacgctccg 480 cagaccccgc gtccggttat cgagggccgt aaaaaacgtc agctgtactc tgctctggct 540 aacaaatgct gccacgttgg ttgcaccaaa cgttctctgg ctcgtttctg cggcggaggt 600 gggagtgaac tggccgcact ggaagctgag ctggctgccc tcgaagctgg aggctctgga 660 gactactggg gccaaggaac cctggtcacc gtctcctcag cctccaccaa gggcccatcg 720 gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 780 ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 840 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 900 gtggtgactg tgccctctag cagcttgggc acccagacct acatctgcaa cgtgaatcac 960 aagcccagca acaccaaggt ggacaagaaa gttgaaccca aatcttgcga caaaactcac 1020 acatgcccac cgtgcccagc acctccagtc gccggaccgt cagtcttcct cttccctcca 1080 aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 1140 gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1200 aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1260 ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 1320 aaaggcctcc caagctccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1380 ccacaggtgt acaccctgcc tccatcccgg gatgagctga ccaagaacca ggtcagcctg 1440 acctgcctgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 1500 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1560 ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1620 tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1680 ggtaaa 1686 <210> 60 <211> 1593 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 60 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaagtg cgggggtggc 360 ggaagcatcg aaggtcgtca cagccagggc acattcacta gcgattatag taaatatctg 420 gattccaagg cagcgcacga ttttgtagag tggctcttga acggaggccc ttcctccgga 480 gctccacctc cgtccggcgg aggtgggagt tgcgaactgg ccgcactgga agctgagctg 540 gctgccctcg aagctggagg ctctggagac tactggggcc aaggaaccct ggtcaccgtc 600 tcctcagcct ccaccaaggg cccatcggtc ttccccctgg caccctcctc caagagcacc 660 tctgggggca cagcggccct gggctgcctg gtcaaggact acttccccga accggtgacg 720 gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 780 tcctcaggac tctactccct cagcagcgtg gtgactgtgc cctctagcag cttgggcacc 840 cagacctaca tctgcaacgt gaatcacaag cccagcaaca ccaaggtgga caagaaagtt 900 gaacccaaat cttgcgacaa aactcacaca tgcccaccgt gcccagcacc tccagtcgcc 960 ggaccgtcag tcttcctctt ccctccaaaa cccaaggaca ccctcatgat ctccccggacc 1020 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 1080 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 1140 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1200 aaggagtaca agtgcaaggt ctccaacaaa ggcctcccaa gctccatcga gaaaaccatc 1260 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgcctcc atcccgggat 1320 gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1380 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1440 gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1500 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1560 acgcagaaga gcctctccct gtctccgggt aaa 1593 <210> 61 <211> 1593 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 61 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaagtg cgggggtggc 360 ggaagcatcg aaggtcgtca cggccagggc acattcacta gcgattatag taaatatctg 420 gattccaagg cagcgcacga ttttgtagag tggctcttga acggaggccc ttcctccgga 480 gctccacctc cgtccggcgg aggtgggagt tgcgaactgg ccgcactgga agctgagctg 540 gctgccctcg aagctggagg ctctggagac tactggggcc aaggaaccct ggtcaccgtc 600 tcctcagcct ccaccaaggg cccatcggtc ttccccctgg caccctcctc caagagcacc 660 tctgggggca cagcggccct gggctgcctg gtcaaggact acttccccga accggtgacg 720 gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 780 tcctcaggac tctactccct cagcagcgtg gtgactgtgc cctctagcag cttgggcacc 840 cagacctaca tctgcaacgt gaatcacaag cccagcaaca ccaaggtgga caagaaagtt 900 gaacccaaat cttgcgacaa aactcacaca tgcccaccgt gcccagcacc tccagtcgcc 960 ggaccgtcag tcttcctctt ccctccaaaa cccaaggaca ccctcatgat ctccccggacc 1020 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 1080 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 1140 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1200 aaggagtaca agtgcaaggt ctccaacaaa ggcctcccaa gctccatcga gaaaaccatc 1260 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgcctcc atcccgggat 1320 gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1380 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1440 gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1500 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1560 acgcagaaga gcctctccct gtctccgggt aaa 1593 <210> 62 <211> 1950 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 62 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg gggtggcgga 360 agcgccccac cacgcctcat ctgtgacagc cgagtcctgg agaggtacct cttggaggcc 420 aaggaggccg agaatatcac gacgggctgt gctgaacact gcagcttgaa tgagaatatc 480 actgtcccag acaccaaagt taatttctat gcctggaaga ggatggaggt cgggcagcag 540 gccgtagaag tctggcaggg cctggccctg ctgtcggaag ctgtcctgcg gggccaggcc 600 ctgttggtca actcttccca gccgtgggag cccctgcagc tgcatgtgga taaagccgtc 660 agtggccttc gcagcctcac cactctgctt cgggctctgg gagcccagaa ggaagccatc 720 tcccctccag atgcggcctc agctgctcca ctccgaacaa tcactgctga cactttccgc 780 aaactcttcc gagtctactc caatttcctc cggggaaagc tgaagctgta cacaggggag 840 gcctgcagga caggggacag aggcggaggt gggagtgaac tggccgcact ggaagctgag 900 ctggctgccc tcgaagctgg aggctctgga gactactggg gccaaggaac cctggtcacc 960 gtctcctcag ccagcactaa aggtccatct gtgttccctc tggctccttg cagccggagc 1020 acctccgagt ccacagccgc tctgggatgt ctggtgaaag attacttccc cgagcccgtc 1080 accgtgagct ggaatagcgg agcactgacc tccggcgtcc acacatccc cgccgtgctc 1140 caaagctccg gcctgtacag cctctcctcc gtggtcaccg tgcccagcag ctctctgggc 1200 acaaagacct atacctgtaa cgtggatcac aagcctagca acaccaaagt ggataagcgg 1260 gtggagagca agtacggccc tccctgtccc ccttgccccg ctcctgaggc cgctggcgga 1320 ccttccgtgt tcctgtttcc ccctaagccc aaggacaccc tcatgattag ccggacaccc 1380 gaagtgacct gcgtggtcgt ggatgtgtcc caggaggacc ctgaagtgca atttaactgg 1440 tacgtggacg gcgtcgaggt gcacaacgcc aagaccaagc ctcgggaaga gcagttcaac 1500 agcacctacc gggtggtcag cgtgctgaca gtgctgcacc aggactggct gaacggcaag 1560 gagtacaagt gcaaggtgag caacaagggc ctgcccagct ccatcgagaa gaccatcagc 1620 aaggccaagg gccagcccag ggaaccccag gtgtataccc tgccccctag ccaggaggaa 1680 atgaccaaaa accaggtgag cctgacctgc ctggtgaagg gcttctaccc cagcgacatc 1740 gccgtggagt gggagagcaa cggccagccc gagaacaatt acaagaccac ccctcctgtg 1800 ctggacagcg acggctcctt ctttctgtat agccggctga ccgtggacaa gagcaggtgg 1860 caggagggca acgtgttctc ctgtagcgtg atgcacgagg ccctgcacaa ccattacacc 1920 cagaagagct tgagcctgag cctgggcaaa 1950 <210> 63 <211> 1293 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 63 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca ggatgtgaat accgcggtcg catggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctattct gcatccttct tgtatagtgg ggtcccatca 180 aggttcagtg gcagtagatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag cattacggcg gaagcggagc aaagctcgcc 300 gcactgaaag ccaagctggc cgctctgaag gggggtggcg gaagcacacc tctgggcccc 360 gcctcctccc tgcctcagag ctttctgctc aaatgtctgg agcaggtgcg gaagatccag 420 ggcgacggcg ccgctctgca agagaaactg tgcgccacat ataagctgtg tcaccccgag 480 gaactggtcc tcttgggcca cagcctgggc atcccctggg cccctctcag ctcctgcccc 540 tcccaagctc tccaactggc tggatgtctg tcccaactgc actccggcct cttcctgtac 600 cagggactcc tccaggctct cgaagggatc agccccgaac tgggccccac actggacacc 660 ttgcaactcg atgtggccga tttcgccaca accatctggc agcagatgga agaactcgga 720 atggctcctg ctctccagcc cacacaggga gctatgcctg ctttcgcctc tgctttccag 780 cggagagctg gtggtgtgct cgtcgcatcc cacctccaga gcttcttgga ggtgtcctat 840 cgggtgctcc ggcatctggc ccaacccggc ggaggtggga gtgaactggc cgcactggaa 900 gctgagctgg ctgccctcga agctggaggc tctggaccga cgttcggcca aggtaccaag 960 cttgagatca aacgaactgt ggctgcacca tctgtcttca tcttcccgcc atctgatgag 1020 cagttgaaat ctggaactgc ctctgtcgtg tgcctgctga ataacttcta tcccaagag 1080 gccaaagtac agtggaaggt ggataacgcc ctccaatcgg gtaactccca ggagagtgtc 1140 acagagcagg acagcaagga cagcacctac agcctcagca gcaccctgac gctgagcaaa 1200 gcagactacg agaaacacaa agtctacgcc tgcgaagtca cccatcaggg cctgtcctcg 1260 cccgtcacaa agagcttcaa caggggagag tgt 1293 <210> 64 <211> 1602 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 64 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg gggtggcgga 360 agcgctgaca acaaatgcga aaactctctg cgtcgtgaaa tcgcttgcgg tcagtgccgt 420 gacaaagtta aaaccgacgg ttacttctac gaatgctgca cctctgactc taccttcaaa 480 aaatgccagg acctgctgca cggcggaggt gggagtgaac tggccgcact ggaagctgag 540 ctggctgccc tcgaagctgg aggctctgga gactactggg gccaaggaac cctggtcacc 600 gtctcctcag cctccaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 660 acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 720 acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 780 cagtcctcag gactctactc cctcagcagc gtggtgactg tgccctctag cagcttgggc 840 acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaaa 900 gttgaaccca aatcttgcga caaaactcac acatgcccac cgtgcccagc acctccagtc 960 gccggaccgt cagtcttcct cttccctcca aaacccaagg acaccctcat gatctcccgg 1020 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 1080 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1140 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1200 ggcaaggagt acaagtgcaa ggtctccaac aaaggcctcc caagctccat cgagaaaacc 1260 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc tccatcccgg 1320 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1380 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1440 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1500 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1560 tacaccgcaga agagcctctc cctgtctccg ggtaaatgat aa 1602 <210> 65 <211> 1614 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 65 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaagtg cgggggtggc 360 ggaagcatcg aaggtcgtca cggcgacggt tcattctctg acgaaatgaa tacaatactc 420 gacaacctcg ccgccaggga ctttatcaat tggctcattc aaactaaaat caccgacgga 480 ggcccttcct ccggagctcc acctccgtcc ggcggaggtg ggagttgcga actggccgca 540 ctggaagctg agctggctgc cctcgaagct ggaggctctg gagactactg gggccaagga 600 accctggtca ccgtctcctc agcctccacc aagggcccat cggtcttccc cctggcaccc 660 tcctccaaga gcacctctgg gggcacagcg gccctgggct gcctggtcaa ggactacttc 720 cccgaaccgg tgacggtgtc gtggaactca ggcgccctga ccagcggcgt gcacaccttc 780 ccggctgtcc tacagtcctc aggactctac tccctcagca gcgtggtgac tgtgccctct 840 agcagcttgg gcacccagac ctacatctgc aacgtgaatc acaagcccag caacaccaag 900 gtggacaaga aagttgaacc caaatcttgc gacaaaactc acacatgccc accgtgccca 960 gcacctccag tcgccggacc gtcagtcttc ctcttccctc caaaacccaa ggacaccctc 1020 atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 1080 gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1140 cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1200 gactggctga atggcaagga gtacaagtgc aaggtctcca acaaaggcct cccaagctcc 1260 atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1320 cctccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1380 ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1440 aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1500 gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1560 ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaatg ataa 1614 <210> 66 <211> 1989 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 66 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggcgga 300 agcggagcaa agctcgccgc actgaaagcc aagctggccg ctctgaaggg aggtggcggg 360 agcgctcctc tgggcggtcc tgaaccagca cagtacgagg aactgacact gttgttccat 420 ggagccttgc agctgggcca ggccctcaac ggcgtgtacc gcgccacaga ggcacgtttg 480 accgaggccg gacacagcct gggtttgtac gacagagccc tggagtttct gggtaccgaa 540 gtgcgtcagg gccaggacgc aactcaggag ctgagaacct ccctctctga gatccaggtg 600 gaggaggacg ccctgcacct gcgcgccgag gcgacagcac gctctttggg agaagttgct 660 cgcgctcagc aggccctgcg tgataccgtg cggagactcc aagttcagct cagaggcgct 720 tggctcggac aggcgcatca ggagttcgag accctgaaag ctcgtgccga caaacagtcc 780 cacctgctgt gggcgctcac cggtcacgtc cagcgccagc aacgcgaaat ggccgagcag 840 cagcaatggc tgcgccaaat ccagcagcgc ctgcataccg cggccctgcc agcgggcgga 900 ggtgggagtg aactggccgc actggaagct gagctggctg ccctcgaagc tggaggctct 960 ggagactact ggggccaagg aaccctggtc accgtctcct cagcctccac caagggccca 1020 tcggtcttcc ccctggcacc ctcctccaag agcacctctg ggggcacagc ggccctgggc 1080 tgcctggtca aggactactt ccccgaaccg gtgacggtgt cgtggaactc aggcgccctg 1140 accagcggcg tgcacacctt cccggctgtc ctacagtcct caggactcta ctccctcagc 1200 agcgtggtga ctgtgccctc tagcagcttg ggcacccaga cctacatctg caacgtgaat 1260 cacaagccca gcaacaccaa ggtggacaag aaagttgaac ccaaatcttg cgacaaaact 1320 cacacatgcc caccgtgccc agcacctcca gtcgccggac cgtcagtctt cctcttccct 1380 ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 1440 gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1500 cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1560 gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 1620 aacaaaggcc tcccaagctc catcgagaaa accatctcca aagccaaagg gcagccccga 1680 gaaccacagg tgtacaccct gcctccatcc cgggatgagc tgaccaagaa ccaggtcagc 1740 ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1800 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1860 ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1920 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1980 ccgggtaaa 1989 <210> 67 <211> 900 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 67 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca ggatgtgaat accgcggtcg catggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctattct gcatccttct tgtatagtgg ggtcccatca 180 aggttcagtg gcagtagatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag ggcggaagcg gagcaaagct cgccgcactg 300 aaagccaagc tggccgctct gaagtgcggg ggtggcggaa gcatcgaagg tcgtcacgga 360 gaaggaacat ttaccagcga cctcagcaag cagatggagg aagaggccgt gaggctgttc 420 atcgagtggc tgaagaacgg cggaccctcc tctggcgctc caccccctag cggcggaggt 480 gggagttgcg aactggccgc actggaagct gagctggctg ccctcgaagc tggaggctct 540 ggaccgacgt tcggccaagg taccaagctt gagatcaaac gaactgtggc tgcaccatct 600 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgtcgtgtgc 660 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 720 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 780 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 840 gaagtcaccc atcagggcct gtcctcgccc gtcacaaaga gcttcaacag gggagagtgt 900 <210> 68 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 68 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Gly Ser Gly Ala 20 25 30 Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala Leu Lys Gly Gly Gly 35 40 45 Gly Ser Ala Pro Arg Leu Ile Cys Asp Ser Arg Val Leu Glu Arg 50 55 60 Tyr Leu Leu Glu Ala Lys Glu Ala Glu Asn Ile Thr Thr Gly Cys Ala 65 70 75 80 Glu His Cys Ser Leu Asn Glu Asn Ile Thr Val Pro Asp Thr Lys Val 85 90 95 Asn Phe Tyr Ala Trp Lys Arg Met Glu Val Gly Gln Gln Ala Val Glu 100 105 110 Val Trp Gln Gly Leu Ala Leu Leu Ser Glu Ala Val Leu Arg Gly Gln 115 120 125 Ala Leu Leu Val Asn Ser Ser Gln Pro Trp Glu Pro Leu Gln Leu His 130 135 140 Val Asp Lys Ala Val Ser Gly Leu Arg Ser Leu Thr Thr Leu Leu Arg 145 150 155 160 Ala Leu Gly Ala Gln Lys Glu Ala Ile Ser Pro Pro Asp Ala Ala Ser 165 170 175 Ala Ala Pro Leu Arg Thr Ile Thr Ala Asp Thr Phe Arg Lys Leu Phe 180 185 190 Arg Val Tyr Ser Asn Phe Leu Arg Gly Lys Leu Lys Leu Tyr Thr Gly 195 200 205 Glu Ala Cys Arg Thr Gly Asp Arg Gly Gly Gly Gly Ser Glu Leu Ala 210 215 220 Ala Leu Glu Ala Glu Leu Ala Ala Ala Leu Glu Ala Gly Gly Ser Gly Thr 225 230 235 240 Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 245 250 255 Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 260 265 270 Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 275 280 285 Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro 290 295 300 Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 305 310 315 320 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 325 330 335 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 340 345 350 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 355 360 365 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 370 375 380 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 385 390 395 400 Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys 405 410 415 Ser Phe Asn Arg Gly Glu Cys 420 <210> 69 <211> 661 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 69 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Thr Pro Leu Gly Pro Ala Arg 115 120 125 Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val Arg Lys 130 135 140 Ile Gln Ala Asp Gly Ala Glu Leu Gln Glu Arg Leu Cys Ala Ala His 145 150 155 160 Lys Leu Cys His Pro Glu Glu Leu Met Leu Leu Arg His Ser Leu Gly 165 170 175 Ile Pro Gln Ala Pro Leu Ser Ser Cys Ser Ser Gln Ser Leu Gln Leu 180 185 190 Thr Ser Cys Leu Asn Gln Leu His Gly Gly Leu Phe Leu Tyr Gln Gly 195 200 205 Leu Leu Gln Ala Leu Ala Gly Ile Ser Pro Glu Leu Ala Pro Thr Leu 210 215 220 Asp Thr Leu Gln Leu Asp Val Thr Asp Phe Ala Thr Asn Ile Trp Leu 225 230 235 240 Gln Met Glu Asp Leu Gly Ala Ala Pro Ala Val Gln Pro Thr Gln Gly 245 250 255 Ala Met Pro Thr Phe Thr Ser Ala Phe Gln Arg Arg Ala Gly Gly Val 260 265 270 Leu Val Ala Ser Gln Leu His Arg Phe Leu Glu Leu Ala Tyr Arg Gly 275 280 285 Leu Arg Tyr Leu Ala Glu Pro Gly Gly Gly Gly Ser Glu Leu Ala Ala 290 295 300 Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Asp Tyr 305 310 315 320 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 325 330 335 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 340 345 350 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 355 360 365 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 370 375 380 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 385 390 395 400 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 405 410 415 Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 420 425 430 Ser Cys Asp Lys Thr His Thr Cys Pro Cys Pro Ala Pro Glu Leu 435 440 445 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 450 455 460 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 465 470 475 480 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 485 490 495 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 500 505 510 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 515 520 525 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 530 535 540 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 545 550 555 560 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 565 570 575 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 580 585 590 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 595 600 605 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 610 615 620 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 625 630 635 640 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 645 650 655 Leu Ser Pro Gly Lys 660 <210> 70 <211> 665 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 70 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala 100 105 110 Lys Leu Ala Ala Leu Lys Gly Gly Gly Gly Ser Thr Pro Leu Gly Pro 115 120 125 Ala Arg Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val 130 135 140 Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu Gln Glu Arg Leu Cys Ala 145 150 155 160 Ala His Lys Leu Cys His Pro Glu Glu Leu Met Leu Leu Arg His Ser 165 170 175 Leu Gly Ile Pro Gln Ala Pro Leu Ser Ser Cys Ser Ser Gln Ser Leu 180 185 190 Gln Leu Thr Ser Cys Leu Asn Gln Leu His Gly Gly Leu Phe Leu Tyr 195 200 205 Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile Ser Pro Glu Leu Ala Pro 210 215 220 Thr Leu Asp Thr Leu Gln Leu Asp Val Thr Asp Phe Ala Thr Asn Ile 225 230 235 240 Trp Leu Gln Met Glu Asp Leu Gly Ala Ala Pro Ala Val Gln Pro Thr 245 250 255 Gln Gly Ala Met Pro Thr Phe Thr Ser Ala Phe Gln Arg Arg Ala Gly 260 265 270 Gly Val Leu Val Ala Ser Gln Leu His Arg Phe Leu Glu Leu Ala Tyr 275 280 285 Arg Gly Leu Arg Tyr Leu Ala Glu Pro Gly Gly Gly Gly Ser Glu Leu 290 295 300 Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly 305 310 315 320 Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser 325 330 335 Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly 340 345 350 Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Ser Tyr 355 360 365 Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser 370 375 380 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 385 390 395 400 Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe 405 410 415 Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala 420 425 430 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 435 440 445 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Lys 450 455 460 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 465 470 475 480 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 485 490 495 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 500 505 510 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 515 520 525 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 530 535 540 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 545 550 555 560 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu 565 570 575 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 580 585 590 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 595 600 605 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 610 615 620 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 625 630 635 640 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 645 650 655 Lys Ser Leu Ser Leu Ser Pro Gly Lys 660 665 <210> 71 <211> 531 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 71 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Cys Gly Gly Gly Gly Ser Ile Glu Gly Arg His Gly 115 120 125 Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala 130 135 140 Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly 145 150 155 160 Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Cys Glu Leu Ala Ala Leu 165 170 175 Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Asp Tyr Trp 180 185 190 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 195 200 205 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 210 215 220 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 225 230 235 240 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 245 250 255 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 260 265 270 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 275 280 285 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 290 295 300 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 305 310 315 320 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 325 330 335 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 340 345 350 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 355 360 365 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 370 375 380 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 385 390 395 400 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 405 410 415 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 420 425 430 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 435 440 445 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 450 455 460 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 465 470 475 480 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 485 490 495 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 500 505 510 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 515 520 525 Pro Gly Lys 530 <210> 72 <211> 521 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 72 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Ile Asn Val Lys Cys Ser Leu 115 120 125 Pro Gln Gln Cys Ile Lys Pro Cys Lys Asp Ala Gly Met Arg Phe Gly 130 135 140 Lys Cys Met Asn Lys Lys Cys Arg Cys Tyr Ser Gly Gly Gly Gly Ser 145 150 155 160 Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly 165 170 175 Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 180 185 190 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 195 200 205 Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 210 215 220 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 225 230 235 240 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 245 250 255 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 260 265 270 Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys 275 280 285 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 290 295 300 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Lys 305 310 315 320 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 325 330 335 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 340 345 350 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 355 360 365 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 370 375 380 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 385 390 395 400 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 405 410 415 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu 420 425 430 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 435 440 445 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 450 455 460 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 465 470 475 480 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 485 490 495 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 500 505 510 Lys Ser Leu Ser Leu Ser Pro Gly Lys 515 520 <210> 73 <211> 523 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 73 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Ala Ala Ala Ile Ser Cys Val 115 120 125 Gly Ser Pro Glu Cys Pro Pro Lys Cys Arg Ala Gln Gly Cys Lys Asn 130 135 140 Gly Lys Cys Met Asn Arg Lys Cys Lys Cys Tyr Tyr Cys Gly Gly Gly 145 150 155 160 Gly Ser Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala 165 170 175 Gly Gly Ser Gly Asp Tyr Trp Gly Gly Gly Thr Leu Val Thr Val Ser 180 185 190 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 195 200 205 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 210 215 220 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 225 230 235 240 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 245 250 255 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 260 265 270 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 275 280 285 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 290 295 300 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 305 310 315 320 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 325 330 335 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 340 345 350 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 355 360 365 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 370 375 380 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 385 390 395 400 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 405 410 415 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 420 425 430 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 435 440 445 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 450 455 460 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 465 470 475 480 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 485 490 495 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 500 505 510 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 515 520 <210> 74 <211> 662 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 74 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Ala Thr Pro Leu Gly Pro Ala 115 120 125 Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val Arg 130 135 140 Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Val Ser Glu 145 150 155 160 Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly 165 170 175 His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln 180 185 190 Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe 195 200 205 Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu 210 215 220 Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr 225 230 235 240 Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln 245 250 255 Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg 260 265 270 Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val 275 280 285 Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Gly Gly Gly Gly Ser 290 295 300 Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly 305 310 315 320 Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 325 330 335 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser 340 345 350 Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 355 360 365 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 370 375 380 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 385 390 395 400 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr 405 410 415 Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 420 425 430 Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 435 440 445 Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 450 455 460 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 465 470 475 480 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 485 490 495 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 500 505 510 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 515 520 525 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 530 535 540 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 545 550 555 560 Pro Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn 565 570 575 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 580 585 590 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 595 600 605 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 610 615 620 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 625 630 635 640 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 645 650 655 Ser Leu Ser Leu Gly Lys 660 <210> 75 <211> 675 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 75 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Phe Pro Thr Ile Pro Leu Ser 115 120 125 Arg Leu Phe Asp Asn Ala Met Leu Arg Ala His Arg Leu His Gln Leu 130 135 140 Ala Phe Asp Thr Tyr Gln Glu Phe Glu Glu Ala Tyr Ile Pro Lys Glu 145 150 155 160 Gln Lys Tyr Ser Phe Leu Gln Asn Pro Gln Thr Ser Leu Cys Phe Ser 165 170 175 Glu Ser Ile Pro Thr Pro Ser Asn Arg Glu Glu Thr Gln Gln Lys Ser 180 185 190 Asn Leu Glu Leu Leu Arg Ile Ser Leu Leu Leu Ile Gln Ser Trp Leu 195 200 205 Glu Pro Val Gln Phe Leu Arg Ser Val Phe Ala Asn Ser Leu Val Tyr 210 215 220 Gly Ala Ser Asp Ser Asn Val Tyr Asp Leu Leu Lys Asp Leu Glu Glu 225 230 235 240 Gly Ile Gln Thr Leu Met Gly Arg Leu Glu Asp Gly Ser Pro Arg Thr 245 250 255 Gly Gln Ile Phe Lys Gln Thr Tyr Ser Lys Phe Asp Thr Asn Ser His 260 265 270 Asn Asp Asp Ala Leu Leu Lys Asn Tyr Gly Leu Leu Tyr Cys Phe Arg 275 280 285 Lys Asp Met Asp Lys Val Glu Thr Phe Leu Arg Ile Val Gln Cys Arg 290 295 300 Ser Val Glu Gly Ser Cys Gly Phe Gly Gly Gly Gly Ser Glu Leu Ala 305 310 315 320 Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Asp 325 330 335 Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 340 345 350 Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 355 360 365 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 370 375 380 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 385 390 395 400 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 405 410 415 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn 420 425 430 Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser 435 440 445 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 450 455 460 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 465 470 475 480 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 485 490 495 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 500 505 510 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 515 520 525 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 530 535 540 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 545 550 555 560 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 565 570 575 Tyr Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 580 585 590 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 595 600 605 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 610 615 620 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 625 630 635 640 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 645 650 655 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 660 665 670 Leu Gly Lys 675 <210> 76 <211> 684 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 76 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys 50 55 60 Ala Lys Leu Ala Ala Leu Lys Gly Gly Gly Gly Ser Phe Pro Thr Ile 65 70 75 80 Pro Leu Ser Arg Leu Phe Asp Asn Ala Met Leu Arg Ala His Arg Leu 85 90 95 His Gln Leu Ala Phe Asp Thr Tyr Gln Glu Phe Glu Glu Ala Tyr Ile 100 105 110 Pro Lys Glu Gln Lys Tyr Ser Phe Leu Gln Asn Pro Gln Thr Ser Leu 115 120 125 Cys Phe Ser Glu Ser Ile Pro Thr Pro Ser Asn Arg Glu Glu Thr Gln 130 135 140 Gln Lys Ser Asn Leu Glu Leu Leu Arg Ile Ser Leu Leu Leu Ile Gln 145 150 155 160 Ser Trp Leu Glu Pro Val Gln Phe Leu Arg Ser Val Phe Ala Asn Ser 165 170 175 Leu Val Tyr Gly Ala Ser Asp Ser Asn Val Tyr Asp Leu Leu Lys Asp 180 185 190 Leu Glu Glu Gly Ile Gln Thr Leu Met Gly Arg Leu Glu Asp Gly Ser 195 200 205 Pro Arg Thr Gly Gln Ile Phe Lys Gln Thr Tyr Ser Lys Phe Asp Thr 210 215 220 Asn Ser His Asn Asp Asp Ala Leu Leu Lys Asn Tyr Gly Leu Leu Tyr 225 230 235 240 Cys Phe Arg Lys Asp Met Asp Lys Val Glu Thr Phe Leu Arg Ile Val 245 250 255 Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe Gly Gly Gly Gly Ser 260 265 270 Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly 275 280 285 Ser Gly Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr 290 295 300 Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser 305 310 315 320 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly 325 330 335 Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 340 345 350 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 355 360 365 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 370 375 380 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 385 390 395 400 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 405 410 415 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 420 425 430 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 435 440 445 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 450 455 460 Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 465 470 475 480 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 485 490 495 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 500 505 510 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 515 520 525 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 530 535 540 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 545 550 555 560 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 565 570 575 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 580 585 590 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 595 600 605 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 610 615 620 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 625 630 635 640 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 645 650 655 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 660 665 670 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 675 680 <210> 77 <211> 676 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 77 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Gly 85 90 95 Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala Leu 100 105 110 Lys Gly Gly Gly Gly Ser Phe Pro Thr Ile Pro Leu Ser Arg Leu Phe 115 120 125 Asp Asn Ala Met Leu Arg Ala His Arg Leu His Gln Leu Ala Phe Asp 130 135 140 Thr Tyr Gln Glu Phe Glu Glu Ala Tyr Ile Pro Lys Glu Gln Lys Tyr 145 150 155 160 Ser Phe Leu Gln Asn Pro Gln Thr Ser Leu Cys Phe Ser Glu Ser Ile 165 170 175 Pro Thr Pro Ser Asn Arg Glu Glu Thr Gln Gln Lys Ser Asn Leu Glu 180 185 190 Leu Leu Arg Ile Ser Leu Leu Leu Ile Gln Ser Trp Leu Glu Pro Val 195 200 205 Gln Phe Leu Arg Ser Val Phe Ala Asn Ser Leu Val Tyr Gly Ala Ser 210 215 220 Asp Ser Asn Val Tyr Asp Leu Leu Lys Asp Leu Glu Glu Gly Ile Gln 225 230 235 240 Thr Leu Met Gly Arg Leu Glu Asp Gly Ser Pro Arg Thr Gly Gln Ile 245 250 255 Phe Lys Gln Thr Tyr Ser Lys Phe Asp Thr Asn Ser His Asn Asp Asp 260 265 270 Ala Leu Leu Lys Asn Tyr Gly Leu Leu Tyr Cys Phe Arg Lys Asp Met 275 280 285 Asp Lys Val Glu Thr Phe Leu Arg Ile Val Gln Cys Arg Ser Val Glu 290 295 300 Gly Ser Cys Gly Phe Gly Gly Gly Gly Ser Glu Leu Ala Ala Leu Glu 305 310 315 320 Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly His Val Asp Val 325 330 335 Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala 340 345 350 Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser 355 360 365 Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val 370 375 380 Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His Thr Phe 385 390 395 400 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val 405 410 415 Thr Val Pro Gly Ser Thr Ser Gly Gin Thr Phe Thr Cys Asn Val Ala 420 425 430 His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro Lys Ser 435 440 445 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 450 455 460 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 465 470 475 480 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 485 490 495 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 500 505 510 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 515 520 525 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 530 535 540 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 545 550 555 560 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 565 570 575 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 580 585 590 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 595 600 605 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 610 615 620 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 625 630 635 640 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 645 650 655 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 660 665 670 Ser Pro Gly Lys 675 <210> 78 <211> 632 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 78 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Val Pro Ile Gln Lys Val Gln 115 120 125 Asp Asp Thr Lys Thr Leu Ile Lys Thr Ile Val Thr Arg Ile Asn Asp 130 135 140 Ile Ser His Thr Gln Ser Val Ser Ser Lys Gln Lys Val Thr Gly Leu 145 150 155 160 Asp Phe Ile Pro Gly Leu His Pro Ile Leu Thr Leu Ser Lys Met Asp 165 170 175 Gln Thr Leu Ala Val Tyr Gln Gln Ile Leu Thr Ser Met Pro Ser Arg 180 185 190 Asn Val Ile Gln Ile Ser Asn Asp Leu Glu Asn Leu Arg Asp Leu Leu 195 200 205 His Val Leu Ala Phe Ser Lys Ser Cys His Leu Pro Trp Ala Ser Gly 210 215 220 Leu Glu Thr Leu Asp Ser Leu Gly Gly Val Leu Glu Ala Ser Gly Tyr 225 230 235 240 Ser Thr Glu Val Val Ala Leu Ser Arg Leu Gln Gly Ser Leu Gln Asp 245 250 255 Met Leu Trp Gln Leu Asp Leu Ser Pro Gly Cys Gly Gly Gly Gly Ser 260 265 270 Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly 275 280 285 Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 290 295 300 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 305 310 315 320 Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 325 330 335 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 340 345 350 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 355 360 365 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 370 375 380 Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys 385 390 395 400 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 405 410 415 Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 420 425 430 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 435 440 445 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 450 455 460 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 465 470 475 480 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 485 490 495 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 500 505 510 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 515 520 525 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 530 535 540 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 545 550 555 560 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 565 570 575 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 580 585 590 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 595 600 605 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 610 615 620 Ser Leu Ser Leu Ser Pro Gly Lys 625 630 <210> 79 <211> 635 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 79 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys 50 55 60 Leu Ala Ala Leu Lys Gly Gly Gly Gly Ser Val Pro Ile Gln Lys Val 65 70 75 80 Gln Asp Asp Thr Lys Thr Leu Ile Lys Thr Ile Val Thr Arg Ile Asn 85 90 95 Asp Ile Ser His Thr Gln Ser Val Ser Ser Lys Gln Lys Val Thr Gly 100 105 110 Leu Asp Phe Ile Pro Gly Leu His Pro Ile Leu Thr Leu Ser Lys Met 115 120 125 Asp Gln Thr Leu Ala Val Tyr Gln Gln Ile Leu Thr Ser Met Pro Ser 130 135 140 Arg Asn Val Ile Gln Ile Ser Asn Asp Leu Glu Asn Leu Arg Asp Leu 145 150 155 160 Leu His Val Leu Ala Phe Ser Lys Ser Cys His Leu Pro Trp Ala Ser 165 170 175 Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly Val Leu Glu Ala Ser Gly 180 185 190 Tyr Ser Thr Glu Val Val Ala Leu Ser Arg Leu Gln Gly Ser Leu Gln 195 200 205 Asp Met Leu Trp Gln Leu Asp Leu Ser Pro Gly Cys Gly Gly Gly Gly 210 215 220 Ser Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly 225 230 235 240 Gly Ser Gly Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile 245 250 255 Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu 260 265 270 Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp 275 280 285 Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 290 295 300 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 305 310 315 320 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 325 330 335 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 340 345 350 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 355 360 365 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 370 375 380 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 385 390 395 400 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 405 410 415 Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro 420 425 430 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 435 440 445 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 450 455 460 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 465 470 475 480 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 485 490 495 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 500 505 510 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 515 520 525 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 530 535 540 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 545 550 555 560 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 565 570 575 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 580 585 590 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 595 600 605 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 610 615 620 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 625 630 635 <210> 80 <211> 403 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 80 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Gly Gly Ser Gly 85 90 95 Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala Leu Lys Gly Gly 100 105 110 Gly Gly Ser Val Pro Ile Gln Lys Val Gln Asp Asp Thr Lys Thr Leu 115 120 125 Ile Lys Thr Ile Val Thr Arg Ile Asn Asp Ile Ser His Thr Gln Ser 130 135 140 Val Ser Ser Lys Gln Lys Val Thr Gly Leu Asp Phe Ile Pro Gly Leu 145 150 155 160 His Pro Ile Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr 165 170 175 Gln Gln Ile Leu Thr Ser Met Pro Ser Arg Asn Val Ile Gln Ile Ser 180 185 190 Asn Asp Leu Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser 195 200 205 Lys Ser Cys His Leu Pro Trp Ala Ser Gly Leu Glu Thr Leu Asp Ser 210 215 220 Leu Gly Gly Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala 225 230 235 240 Leu Ser Arg Leu Gln Gly Ser Leu Gln Asp Met Leu Trp Gln Leu Asp 245 250 255 Leu Ser Pro Gly Cys Gly Gly Gly Gly Ser Glu Leu Ala Ala Leu Glu 260 265 270 Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Pro Thr Phe Gly 275 280 285 Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 290 295 300 Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser 305 310 315 320 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 325 330 335 Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 340 345 350 Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 355 360 365 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 370 375 380 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 385 390 395 400 Gly Glu Cys <210> 81 <211> 649 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 81 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Cys Asp Leu Pro Gln Thr His 115 120 125 Ser Leu Gly Ser Arg Arg Thr Leu Met Leu Leu Ala Gln Met Arg Arg 130 135 140 Ile Ser Leu Phe Ser Cys Leu Lys Asp Arg His Asp Phe Gly Phe Pro 145 150 155 160 Gln Glu Glu Phe Gly Asn Gln Phe Gln Lys Ala Glu Thr Ile Pro Val 165 170 175 Leu His Glu Met Ile Gln Gln Ile Phe Asn Leu Phe Ser Thr Lys Asp 180 185 190 Ser Ser Ala Ala Trp Asp Glu Thr Leu Leu Asp Lys Phe Tyr Thr Glu 195 200 205 Leu Tyr Gln Gln Leu Asn Asp Leu Glu Ala Cys Val Ile Gln Gly Val 210 215 220 Gly Val Thr Glu Thr Pro Leu Met Lys Glu Asp Ser Ile Leu Ala Val 225 230 235 240 Arg Lys Tyr Phe Gln Arg Ile Thr Leu Tyr Leu Lys Glu Lys Lys Tyr 245 250 255 Ser Pro Cys Ala Trp Glu Val Val Arg Ala Glu Ile Met Arg Ser Phe 260 265 270 Ser Leu Ser Thr Asn Leu Gln Glu Ser Leu Arg Ser Lys Glu Gly Gly 275 280 285 Gly Gly Ser Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu 290 295 300 Ala Gly Gly Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 305 310 315 320 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 325 330 335 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 340 345 350 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 355 360 365 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 370 375 380 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 385 390 395 400 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 405 410 415 Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro 420 425 430 Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Lys 435 440 445 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 450 455 460 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 465 470 475 480 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 485 490 495 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 500 505 510 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 515 520 525 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 530 535 540 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 545 550 555 560 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 565 570 575 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 580 585 590 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 595 600 605 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 610 615 620 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 625 630 635 640 Lys Ser Leu Ser Leu Ser Leu Gly Lys 645 <210> 82 <211> 652 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 82 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Met Ser Tyr Asn Leu Leu Gly 115 120 125 Phe Leu Gln Arg Ser Ser Asn Phe Gln Cys Gln Lys Leu Leu Trp Gln 130 135 140 Leu Asn Gly Arg Leu Glu Tyr Cys Leu Lys Asp Arg Met Asn Phe Asp 145 150 155 160 Ile Pro Glu Glu Ile Lys Gln Leu Gln Gln Phe Gln Lys Glu Asp Ala 165 170 175 Ala Leu Thr Ile Tyr Glu Met Leu Gln Asn Ile Phe Ala Ile Phe Arg 180 185 190 Gln Asp Ser Ser Ser Thr Gly Trp Asn Glu Thr Ile Val Glu Asn Leu 195 200 205 Leu Ala Asn Val Tyr His Gln Ile Asn His Leu Lys Thr Val Leu Glu 210 215 220 Glu Lys Leu Glu Lys Glu Asp Phe Thr Arg Gly Lys Leu Met Ser Ser 225 230 235 240 Leu His Leu Lys Arg Tyr Tyr Gly Arg Ile Leu His Tyr Leu Lys Ala 245 250 255 Lys Glu Tyr Ser His Cys Ala Trp Thr Ile Val Arg Val Glu Ile Leu 260 265 270 Arg Asn Phe Tyr Phe Ile Asn Arg Leu Thr Gly Tyr Leu Arg Asn Gly 275 280 285 Gly Gly Gly Ser Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu 290 295 300 Glu Ala Gly Gly Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 305 310 315 320 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 325 330 335 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 340 345 350 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 355 360 365 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 370 375 380 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 385 390 395 400 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 405 410 415 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 420 425 430 Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 435 440 445 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 450 455 460 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 465 470 475 480 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 485 490 495 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 500 505 510 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 515 520 525 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 530 535 540 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 545 550 555 560 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 565 570 575 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 580 585 590 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 595 600 605 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 610 615 620 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 625 630 635 640 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 645 650 <210> 83 <211> 651 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 83 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Gly 85 90 95 Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala Leu 100 105 110 Lys Gly Gly Gly Gly Ser Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln 115 120 125 Arg Ser Ser Asn Phe Gln Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly 130 135 140 Arg Leu Glu Tyr Cys Leu Lys Asp Arg Met Asn Phe Asp Ile Pro Glu 145 150 155 160 Glu Ile Lys Gln Leu Gln Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr 165 170 175 Ile Tyr Glu Met Leu Gln Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser 180 185 190 Ser Ser Thr Gly Trp Asn Glu Thr Ile Val Glu Asn Leu Leu Ala Asn 195 200 205 Val Tyr His Gln Ile Asn His Leu Lys Thr Val Leu Glu Glu Lys Leu 210 215 220 Glu Lys Glu Asp Phe Thr Arg Gly Lys Leu Met Ser Ser Leu His Leu 225 230 235 240 Lys Arg Tyr Tyr Gly Arg Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr 245 250 255 Ser His Cys Ala Trp Thr Ile Val Arg Val Glu Ile Leu Arg Asn Phe 260 265 270 Tyr Phe Ile Asn Arg Leu Thr Gly Tyr Leu Arg Asn Gly Gly Gly Gly 275 280 285 Ser Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly 290 295 300 Gly Ser Gly His Val Asp Val Trp Gly Gin Gly Leu Leu Val Thr Val 305 310 315 320 Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys 325 330 335 Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser 340 345 350 Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu 355 360 365 Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 370 375 380 Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln 385 390 395 400 Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp 405 410 415 Lys Ala Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 420 425 430 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 435 440 445 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 450 455 460 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 465 470 475 480 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 485 490 495 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 500 505 510 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 515 520 525 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 530 535 540 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 545 550 555 560 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 565 570 575 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 580 585 590 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 595 600 605 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 610 615 620 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 625 630 635 640 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 645 650 <210> 84 <211> 522 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 84 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Cys Gly Gly Gly Gly Ser Ile Glu Gly Arg His Ala 115 120 125 Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala 130 135 140 Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly Gly Gly 145 150 155 160 Ser Cys Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala 165 170 175 Gly Gly Ser Gly Asp Tyr Trp Gly Gly Gly Thr Leu Val Thr Val Ser 180 185 190 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 195 200 205 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 210 215 220 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 225 230 235 240 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 245 250 255 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 260 265 270 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 275 280 285 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 290 295 300 Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro 305 310 315 320 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 325 330 335 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 340 345 350 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 355 360 365 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 370 375 380 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 385 390 395 400 Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 405 410 415 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 420 425 430 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 435 440 445 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 450 455 460 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 465 470 475 480 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 485 490 495 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 500 505 510 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 515 520 <210> 85 <211> 543 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 85 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Ala Gln Glu Pro Val Lys Gly 115 120 125 Pro Val Ser Thr Lys Pro Gly Ser Cys Pro Ile Ile Leu Ile Arg Cys 130 135 140 Ala Met Leu Asn Pro Pro Asn Arg Cys Leu Lys Asp Thr Asp Cys Pro 145 150 155 160 Gly Ile Lys Lys Cys Cys Glu Gly Ser Cys Gly Met Ala Cys Phe Val 165 170 175 Pro Gln Gly Gly Gly Gly Ser Glu Leu Ala Ala Leu Glu Ala Glu Leu 180 185 190 Ala Ala Leu Glu Ala Gly Gly Ser Gly Asp Tyr Trp Gly Gln Gly Thr 195 200 205 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 210 215 220 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 225 230 235 240 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 245 250 255 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 260 265 270 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 275 280 285 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 290 295 300 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 305 310 315 320 His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 325 330 335 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 340 345 350 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 355 360 365 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 370 375 380 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 385 390 395 400 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 405 410 415 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 420 425 430 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 435 440 445 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 450 455 460 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 465 470 475 480 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 485 490 495 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 500 505 510 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 515 520 525 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 530 535 540 <210> 86 <211> 578 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 86 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Asp Ser Trp Met Glu Glu Val 115 120 125 Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys 130 135 140 Gly Met Ser Thr Trp Ser Lys Arg Glu Ala Glu Asp Leu Gln Val Gly 145 150 155 160 Gln Val Glu Leu Gly Gly Gly Pro Gly Ala Gly Ser Leu Gln Pro Leu 165 170 175 Ala Leu Glu Gly Ser Leu Gln Lys Arg Arg Lys Lys Arg Gln Leu Tyr 180 185 190 Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser 195 200 205 Leu Ala Arg Phe Cys Gly Gly Gly Gly Ser Glu Leu Ala Ala Leu Glu 210 215 220 Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Asp Tyr Trp Gly 225 230 235 240 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 245 250 255 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 260 265 270 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 275 280 285 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 290 295 300 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 305 310 315 320 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 325 330 335 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 340 345 350 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 385 390 395 400 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 465 470 475 480 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 485 490 495 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 565 570 575 Gly Lys <210> 87 <211> 540 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 87 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala 100 105 110 Ala Leu Lys Gly Gly Gly Gly Ser Leu Lys Cys Tyr Gln His Gly Lys 115 120 125 Val Val Thr Cys His Arg Asp Met Lys Phe Cys Tyr His Asn Thr Gly 130 135 140 Met Pro Phe Arg Asn Leu Lys Leu Ile Leu Gln Gly Cys Ser Ser Ser 145 150 155 160 Cys Ser Glu Thr Glu Asn Asn Lys Cys Cys Ser Thr Asp Arg Cys Asn 165 170 175 Lys Gly Gly Gly Gly Ser Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala 180 185 190 Ala Leu Glu Ala Gly Gly Ser Gly Trp Gly Gln Gly Thr Leu Val Thr 195 200 205 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 210 215 220 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 225 230 235 240 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 245 250 255 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 260 265 270 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 275 280 285 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 290 295 300 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 305 310 315 320 Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 325 330 335 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 340 345 350 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 355 360 365 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 370 375 380 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 385 390 395 400 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 405 410 415 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 420 425 430 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 435 440 445 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 450 455 460 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 465 470 475 480 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 485 490 495 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 500 505 510 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 515 520 525 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 530 535 540 <210> 88 <211> 547 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 88 Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala 100 105 110 Lys Leu Ala Ala Leu Lys Gly Gly Gly Gly Ser Leu Lys Cys Tyr Gln 115 120 125 His Gly Lys Val Val Thr Cys His Arg Asp Met Lys Phe Cys Tyr His 130 135 140 Asn Thr Gly Met Pro Phe Arg Asn Leu Lys Leu Ile Leu Gln Gly Cys 145 150 155 160 Ser Ser Ser Cys Ser Glu Thr Glu Asn Asn Lys Cys Cys Ser Thr Asp 165 170 175 Arg Cys Asn Lys Gly Gly Gly Gly Ser Glu Leu Ala Ala Leu Glu Ala 180 185 190 Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Tyr Phe Asp Val Trp 195 200 205 Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 210 215 220 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 225 230 235 240 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 245 250 255 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 260 265 270 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 275 280 285 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 290 295 300 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 305 310 315 320 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 325 330 335 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 340 345 350 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 355 360 365 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 370 375 380 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 385 390 395 400 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 405 410 415 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 420 425 430 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 435 440 445 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 450 455 460 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 465 470 475 480 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 485 490 495 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 500 505 510 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 515 520 525 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 530 535 540 Pro Gly Lys 545 <210> 89 <211> 553 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 89 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Asp Ser Trp Met Glu Glu Val 115 120 125 Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys 130 135 140 Gly Met Ser Thr Trp Ser Lys Arg Ser Leu Ser Gln Glu Ile Glu Gly 145 150 155 160 Arg Lys Lys Arg Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His 165 170 175 Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys Gly Gly Gly Gly 180 185 190 Ser Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly 195 200 205 Gly Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 210 215 220 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 225 230 235 240 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 245 250 255 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 260 265 270 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 275 280 285 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 290 295 300 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 305 310 315 320 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 325 330 335 Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 340 345 350 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 355 360 365 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 370 375 380 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 385 390 395 400 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 405 410 415 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 420 425 430 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 435 440 445 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu 450 455 460 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 465 470 475 480 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 485 490 495 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 500 505 510 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 515 520 525 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 530 535 540 Lys Ser Leu Ser Leu Ser Pro Gly Lys 545 550 <210> 90 <211> 562 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 90 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Asp Ser Trp Met Glu Glu Val 115 120 125 Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys 130 135 140 Gly Met Ser Thr Trp Ser Lys Arg Ser Leu Ser Gln Glu Asp Ala Pro 145 150 155 160 Gln Thr Pro Arg Pro Val Ile Glu Gly Arg Lys Lys Arg Gln Leu Tyr 165 170 175 Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser 180 185 190 Leu Ala Arg Phe Cys Gly Gly Gly Gly Ser Glu Leu Ala Ala Leu Glu 195 200 205 Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Asp Tyr Trp Gly 210 215 220 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 225 230 235 240 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 245 250 255 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 260 265 270 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 275 280 285 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 290 295 300 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 305 310 315 320 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 325 330 335 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly 340 345 350 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 355 360 365 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 370 375 380 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 385 390 395 400 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 405 410 415 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 420 425 430 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 435 440 445 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 450 455 460 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 465 470 475 480 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 485 490 495 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 500 505 510 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 515 520 525 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 530 535 540 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 545 550 555 560 Gly Lys <210> 91 <211> 531 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 91 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Cys Gly Gly Gly Gly Ser Ile Glu Gly Arg His Ser 115 120 125 Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Lys Ala 130 135 140 Ala His Asp Phe Val Glu Trp Leu Leu Asn Gly Gly Pro Ser Ser Gly 145 150 155 160 Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Cys Glu Leu Ala Ala Leu 165 170 175 Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Asp Tyr Trp 180 185 190 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 195 200 205 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 210 215 220 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 225 230 235 240 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 245 250 255 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 260 265 270 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 275 280 285 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 290 295 300 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 305 310 315 320 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 325 330 335 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 340 345 350 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 355 360 365 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 370 375 380 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 385 390 395 400 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 405 410 415 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 420 425 430 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 435 440 445 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 450 455 460 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 465 470 475 480 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 485 490 495 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 500 505 510 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 515 520 525 Pro Gly Lys 530 <210> 92 <211> 531 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 92 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Cys Gly Gly Gly Gly Ser Ile Glu Gly Arg His Gly 115 120 125 Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Lys Ala 130 135 140 Ala His Asp Phe Val Glu Trp Leu Leu Asn Gly Gly Pro Ser Ser Gly 145 150 155 160 Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Cys Glu Leu Ala Ala Leu 165 170 175 Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Asp Tyr Trp 180 185 190 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 195 200 205 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 210 215 220 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 225 230 235 240 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 245 250 255 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 260 265 270 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 275 280 285 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 290 295 300 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 305 310 315 320 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 325 330 335 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 340 345 350 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 355 360 365 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 370 375 380 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 385 390 395 400 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 405 410 415 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 420 425 430 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 435 440 445 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 450 455 460 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 465 470 475 480 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 485 490 495 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 500 505 510 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 515 520 525 Pro Gly Lys 530 <210> 93 <211> 650 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 93 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Ala Pro Pro Arg Leu Ile Cys 115 120 125 Asp Ser Arg Val Leu Glu Arg Tyr Leu Leu Glu Ala Lys Glu Ala Glu 130 135 140 Asn Ile Thr Thr Gly Cys Ala Glu His Cys Ser Leu Asn Glu Asn Ile 145 150 155 160 Thr Val Pro Asp Thr Lys Val Asn Phe Tyr Ala Trp Lys Arg Met Glu 165 170 175 Val Gly Gln Gln Ala Val Glu Val Trp Gln Gly Leu Ala Leu Leu Ser 180 185 190 Glu Ala Val Leu Arg Gly Gln Ala Leu Leu Val Asn Ser Ser Gln Pro 195 200 205 Trp Glu Pro Leu Gln Leu His Val Asp Lys Ala Val Ser Gly Leu Arg 210 215 220 Ser Leu Thr Thr Leu Leu Arg Ala Leu Gly Ala Gln Lys Glu Ala Ile 225 230 235 240 Ser Pro Pro Asp Ala Ala Ser Ala Ala Pro Leu Arg Thr Ile Thr Ala 245 250 255 Asp Thr Phe Arg Lys Leu Phe Arg Val Tyr Ser Asn Phe Leu Arg Gly 260 265 270 Lys Leu Lys Leu Tyr Thr Gly Glu Ala Cys Arg Thr Gly Asp Arg Gly 275 280 285 Gly Gly Gly Ser Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu 290 295 300 Glu Ala Gly Gly Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 305 310 315 320 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 325 330 335 Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val 340 345 350 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 355 360 365 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 370 375 380 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 385 390 395 400 Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys 405 410 415 Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys 420 425 430 Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 435 440 445 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 450 455 460 Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp 465 470 475 480 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 485 490 495 Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 500 505 510 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 515 520 525 Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 530 535 540 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu 545 550 555 560 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 565 570 575 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 580 585 590 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 595 600 605 Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn 610 615 620 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 625 630 635 640 Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 645 650 <210> 94 <211> 431 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 94 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Gly Gly Ser Gly 85 90 95 Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala Leu Lys Gly Gly 100 105 110 Gly Gly Ser Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe 115 120 125 Leu Leu Lys Cys Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala 130 135 140 Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu 145 150 155 160 Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu 165 170 175 Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln 180 185 190 Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu 195 200 205 Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp 210 215 220 Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly 225 230 235 240 Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala 245 250 255 Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu 260 265 270 Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln 275 280 285 Pro Gly Gly Gly Gly Ser Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala 290 295 300 Ala Leu Glu Ala Gly Gly Ser Gly Pro Thr Phe Gly Gln Gly Thr Lys 305 310 315 320 Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 325 330 335 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 340 345 350 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 355 360 365 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 370 375 380 Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 385 390 395 400 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln 405 410 415 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 420 425 430 <210> 95 <211> 532 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 95 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Ala Asp Asn Lys Cys Glu Asn 115 120 125 Ser Leu Arg Arg Glu Ile Ala Cys Gly Gln Cys Arg Asp Lys Val Lys 130 135 140 Thr Asp Gly Tyr Phe Tyr Glu Cys Cys Thr Ser Asp Ser Thr Phe Lys 145 150 155 160 Lys Cys Gln Asp Leu Leu His Gly Gly Gly Gly Ser Glu Leu Ala Ala 165 170 175 Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Asp Tyr 180 185 190 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 195 200 205 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 210 215 220 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 225 230 235 240 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 245 250 255 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 260 265 270 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 275 280 285 Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 290 295 300 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val 305 310 315 320 Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 325 330 335 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 340 345 350 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 355 360 365 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 370 375 380 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 385 390 395 400 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 405 410 415 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 420 425 430 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 435 440 445 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 450 455 460 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 465 470 475 480 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 485 490 495 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 500 505 510 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 515 520 525 Ser Pro Gly Lys 530 <210> 96 <211> 536 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 96 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Cys Gly Gly Gly Gly Ser Ile Glu Gly Arg His Gly 115 120 125 Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn Leu Ala 130 135 140 Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr Asp Gly 145 150 155 160 Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Cys 165 170 175 Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly 180 185 190 Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 195 200 205 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 210 215 220 Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 225 230 235 240 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 245 250 255 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 260 265 270 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 275 280 285 Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys 290 295 300 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 305 310 315 320 Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 325 330 335 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 340 345 350 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 355 360 365 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 370 375 380 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 385 390 395 400 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 405 410 415 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 420 425 430 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 435 440 445 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 450 455 460 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 465 470 475 480 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 485 490 495 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 500 505 510 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 515 520 525 Ser Leu Ser Leu Ser Pro Gly Lys 530 535 <210> 97 <211> 663 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 97 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Ala Pro Leu Gly Gly Pro Glu 115 120 125 Pro Ala Gln Tyr Glu Glu Leu Thr Leu Leu Phe His Gly Ala Leu Gln 130 135 140 Leu Gly Gln Ala Leu Asn Gly Val Tyr Arg Ala Thr Glu Ala Arg Leu 145 150 155 160 Thr Glu Ala Gly His Ser Leu Gly Leu Tyr Asp Arg Ala Leu Glu Phe 165 170 175 Leu Gly Thr Glu Val Arg Gln Gly Gln Asp Ala Thr Gln Glu Leu Arg 180 185 190 Thr Ser Leu Ser Glu Ile Gln Val Glu Glu Asp Ala Leu His Leu Arg 195 200 205 Ala Glu Ala Thr Ala Arg Ser Leu Gly Glu Val Ala Arg Ala Gln Gln 210 215 220 Ala Leu Arg Asp Thr Val Arg Arg Leu Gln Val Gln Leu Arg Gly Ala 225 230 235 240 Trp Leu Gly Gln Ala His Gln Glu Phe Glu Thr Leu Lys Ala Arg Ala 245 250 255 Asp Lys Gln Ser His Leu Leu Trp Ala Leu Thr Gly His Val Gln Arg 260 265 270 Gln Gln Arg Glu Met Ala Glu Gln Gln Gln Trp Leu Arg Gln Ile Gln 275 280 285 Gln Arg Leu His Thr Ala Ala Leu Pro Ala Gly Gly Gly Gly Ser Glu 290 295 300 Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser 305 310 315 320 Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 325 330 335 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 340 345 350 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 355 360 365 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 370 375 380 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 385 390 395 400 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 405 410 415 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 420 425 430 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 435 440 445 Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 450 455 460 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 465 470 475 480 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 485 490 495 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 500 505 510 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 515 520 525 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 530 535 540 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gly Gln Pro Arg 545 550 555 560 Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys 565 570 575 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 580 585 590 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 595 600 605 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 610 615 620 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 625 630 635 640 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 645 650 655 Leu Ser Leu Ser Pro Gly Lys 660 <210> 98 <211> 302 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 98 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Gly Ser Gly Ala 20 25 30 Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala Leu Lys Cys Gly Gly 35 40 45 Gly Gly Ser Ile Glu Gly Arg His Gly Glu Gly Thr Phe Thr Ser Asp 50 55 60 Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp 65 70 75 80 Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Gly Gly 85 90 95 Gly Gly Ser Cys Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu 100 105 110 Glu Ala Gly Gly Ser Gly Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro 115 120 125 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser 130 135 140 Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr 145 150 155 160 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 165 170 175 Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu 180 185 190 Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro 195 200 205 Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu 210 215 220 Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn 225 230 235 240 Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser 245 250 255 Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala 260 265 270 Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly 275 280 285 Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 290 295 300 <210> 99 <211> 648 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 99 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Gly 85 90 95 Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala Leu 100 105 110 Lys Gly Gly Gly Gly Ser Asp Ser Trp Met Glu Glu Val Ile Lys Leu 115 120 125 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 130 135 140 Thr Trp Ser Ile Glu Gly Arg Ser Leu Ser Gln Glu Asp Ala Pro Gln 145 150 155 160 Thr Pro Arg Pro Val Ala Glu Ile Val Pro Ser Phe Ile Asn Lys Asp 165 170 175 Thr Glu Thr Ile Asn Met Met Ser Glu Phe Val Ala Asn Leu Pro Gln 180 185 190 Glu Leu Lys Leu Thr Leu Ser Glu Met Gln Pro Ala Leu Pro Gln Leu 195 200 205 Gln Gln His Val Pro Val Leu Lys Asp Ser Ser Leu Leu Phe Glu Glu 210 215 220 Phe Lys Lys Leu Ile Arg Asn Arg Gln Ser Glu Ala Ala Asp Ser Ser 225 230 235 240 Pro Ser Glu Leu Lys Tyr Leu Gly Leu Asp Thr His Ser Ile Glu Gly 245 250 255 Arg Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys 260 265 270 Thr Lys Arg Ser Leu Ala Arg Phe Cys Gly Gly Gly Gly Ser Glu Leu 275 280 285 Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly 290 295 300 His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala 305 310 315 320 Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp 325 330 335 Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Ser Tyr Met 340 345 350 Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly 355 360 365 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 370 375 380 Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gin Thr Phe Thr 385 390 395 400 Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val 405 410 415 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 420 425 430 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Lys Pro 435 440 445 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 450 455 460 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 465 470 475 480 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 485 490 495 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 500 505 510 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 515 520 525 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 530 535 540 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 545 550 555 560 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 565 570 575 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 580 585 590 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 595 600 605 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 610 615 620 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 625 630 635 640 Ser Leu Ser Leu Ser Pro Gly Lys 645 <210> 100 <211> 1161 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 100 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca ggggggtggc ggaagcgccc caccacgcct catctgtgac 120 agccgagtcc tggagaggta cctcttggag gccaaggagg ccgagaatat cacgacgggc 180 tgtgctgaac actgcagctt gaatgagaat atcactgtcc cagacaccaa agttaatttc 240 tatgcctgga agaggatgga ggtcgggcag caggccgtag aagtctggca gggcctggcc 300 ctgctgtcgg aagctgtcct gcggggccag gccctgttgg tcaactcttc ccagccgtgg 360 gagcccctgc agctgcatgt ggataaagcc gtcagtggcc ttcgcagcct caccactctg 420 cttcgggctc tgggagccca gaaggaagcc atctcccctc cagatgcggc ctcagctgct 480 ccactccgaa caatcactgc tgacactttc cgcaaactct tccgagtcta ctccaatttc 540 ctccggggaa agctgaagct gtacacaggg gaggcctgca ggacagggga cagaggcgga 600 ggtgggagta ccgcggtcgc atggtatcag cagaaaccag ggaaagcccc taagctcctg 660 atctattctg catccttctt gtatagtggg gtcccatcaa ggttcagtgg cagtagatct 720 gggacagatt tcactctcac catcagcagt ctgcaacctg aagattttgc aacttactac 780 tgtcaacagc attacactac ccctccgacg ttcggccaag gtaccaagct tgagatcaaa 840 cgaactgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 900 ggaactgcct ctgtcgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 960 tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 1020 agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 1080 aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgtcctcgcc cgtcacaaag 1140 agcttcaaca ggggagagtg t 1161 <210> 101 <211> 1902 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 101 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagatggggc 300 ggtgacggag gcggtggctc cacccccctt ggccctgccc gatccctgcc ccagagcttc 360 ctgctcaagt gcttagagca agtgaggaaa atccaggctg atggcgccga gctgcaggag 420 aggctgtgtg ccgcccacaa gctgtgccac ccggaggagc tgatgctgct caggcactct 480 ctgggcatcc cccaggctcc cctaagcagc tgctccagcc agtccctgca gctgacgagc 540 tgcctgaacc aactacacgg cggcctcttt ctctaccagg gcctcctgca ggccctggcg 600 ggcatctccc cagagctggc ccccaccttg gacacactgc agctggacgt cactgacttt 660 gccacgaaca tctggctgca gatggaggac ctgggggcgg cccccgctgt gcagcccacc 720 cagggcgcca tgccgacctt cacttcagcc ttccaacgca gagcaggagg ggtcctggtt 780 gcttcccagc tgcatcgttt cctggagctg gcataccgtg gcctgcgcta ccttgctgag 840 cccggcggtg gcggaagcgg cttctatgcc atggactact ggggccaagg aaccctggtc 900 accgtctcct cagcctccac caagggccca tcggtcttcc ccctggcacc ctcctccaag 960 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 1020 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 1080 ctacagtcct caggactcta ctccctcagc agcgtggtga ctgtgccctc tagcagcttg 1140 ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 1200 aaagttgaac ccaaatcttg cgacaaaact cacacatgcc caccgtgccc agcacctgaa 1260 ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 1320 tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 1380 aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 1440 gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1500 ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 1560 aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 1620 tcccgggatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1680 cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1740 acgcctcccg tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac 1800 aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1860 aaccactaca cgcagaagag cctctccctg tctccgggta aa 1902 <210> 102 <211> 1488 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 102 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagatgcggg 300 ggtggcggaa gcatcgaagg tcgtcacgga gaaggaacat ttaccagcga cctcagcaag 360 cagatggagg aagaggccgt gaggctgttc atcgagtggc tgaagaacgg cggaccctcc 420 tctggcgctc caccccctag cggcggaggt gggagttgcg actactgggg ccaaggaacc 480 ctggtcaccg tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 540 tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 600 gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 660 gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgactgt gccctctagc 720 agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 780 gacaagaaag ttgaacccaa atcttgcgac aaaactcaca catgcccacc gtgcccagca 840 cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 900 atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 960 gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1020 cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1080 gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1140 atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1200 cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1260 ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1320 aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1380 gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1440 ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1488 <210> 103 <211> 1455 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 103 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggaggc 300 ggtggctcca tcaacgtgaa gtgcagcctg ccccagcagt gcatcaagcc ctgcaaggac 360 gccggcatgc ggttcggcaa gtgcatgaac aagaagtgca ggtgctacag cggcggtggc 420 ggaagcgact actggggcca aggaaccctg gtcaccgtct cctcagcctc caccaagggc 480 ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 540 ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 600 ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 660 agcagcgtgg tgactgtgcc ctctagcagc ttgggcaccc agacctacat ctgcaacgtg 720 aatcacaagc ccagcaacac caaggtggac aagaaagttg aacccaaatc ttgcgacaaa 780 actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 840 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 900 gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 960 gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 1020 gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 1080 gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1140 ccccgagaac cacaggtgta caccctgccc ccatccggg atgagctgac caagaaccag 1200 gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1260 agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1320 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1380 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1440 ctgtctccgg gtaaa 1455 <210> 104 <211> 1461 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 104 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggaggc 300 ggtggctccg ccgctgcaat ctcctgcgtc ggcagccccg aatgtcctcc caagtgccgg 360 gctcagggat gcaagaacgg caagtgtatg aaccggaagt gcaagtgcta ctattgcggc 420 ggtggcggaa gcgactactg gggccaagga accctggtca ccgtctcctc agcctccacc 480 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 540 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 600 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 660 tccctcagca gcgtggtgac tgtgccctct agcagcttgg gcacccagac ctacatctgc 720 aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgaacc caaatcttgc 780 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 840 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 900 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 960 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 1020 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1080 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1140 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 1200 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1260 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1320 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1380 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1440 ctctccctgt ctccgggtaa a 1461 <210> 105 <211> 1878 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 105 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagggggt 300 ggcggaagcg ccacacctct gggccccgcc tcctccctgc ctcagagctt tctgctcaaa 360 tgtctggagc aggtgcggaa gatccagggc gacggcgccg ctctgcaaga gaaactggtc 420 agcgaatgcg ccacatataa gctgtgtcac cccgaggaac tggtcctctt gggccacagc 480 ctgggcatcc cctgggcccc tctcagctcc tgcccctccc aagctctcca actggctgga 540 tgtctgtccc aactgcactc cggcctcttc ctgtaccagg gactcctcca ggctctcgaa 600 gggatcagcc ccgaactggg ccccacactg gacaccttgc aactcgatgt ggccgatttc 660 gccacaacca tctggcagca gatggaagaa ctcggaatgg ctcctgctct ccagcccaca 720 cagggagcta tgcctgcttt cgcctctgct ttccagcgga gagctggtgg tgtgctcgtc 780 gcatcccacc tccagagctt cttggaggtg tcctatcggg tgctccggca tctggcccaa 840 cccggcggag gtgggagtga ctactggggc caaggaaccc tggtcaccgt ctcctcagcc 900 agcactaaag gtccatctgt gttccctctg gctccttgca gccggagcac ctccgagtcc 960 acagccgctc tgggatgtct ggtgaaagat tacttccccg agcccgtcac cgtgagctgg 1020 aatagcggag cactgacctc cggcgtccac acatccccg ccgtgctcca aagctccggc 1080 ctgtacagcc tctcctccgt ggtcaccgtg cccagcagct ctctgggcac aaagacctat 1140 acctgtaacg tggatcacaa gcctagcaac accaaagtgg ataagcgggt ggagagcaag 1200 tacggccctc cctgtccccc ttgccccgct cctgaggccg ctggcggacc ttccgtgttc 1260 ctgtttcccc ctaagcccaa ggacaccctc atgattagcc ggacacccga agtgacctgc 1320 gtggtcgtgg atgtgtccca ggaggaccct gaagtgcaat ttaactggta cgtggacggc 1380 gtcgaggtgc acaacgccaa gaccaagcct cgggaagagc agttcaacag cacctaccgg 1440 gtggtcagcg tgctgacagt gctgcaccag gactggctga acggcaagga gtacaagtgc 1500 aaggtgagca acaagggcct gcccagctcc atcgagaaga ccatcagcaa ggccaagggc 1560 cagcccaggg aaccccaggt gtataccctg ccccctagcc aggaggaaat gaccaaaaac 1620 caggtgagcc tgacctgcct ggtgaagggc ttctacccca gcgacatcgc cgtggagtgg 1680 gagagcaacg gccagcccga gaacaattac aagaccaccc ctcctgtgct ggacagcgac 1740 ggctccttct ttctgtatag ccggctgacc gtggacaaga gcaggtggca ggagggcaac 1800 gtgttctcct gtagcgtgat gcacgaggcc ctgcacaacc attacaccca gaagagcttg 1860 agcctgagcc tgggcaaa 1878 <210> 106 <211> 1917 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 106 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagggggt 300 ggcggaagct tcccaaccat tcccttatcc aggctttttg acaacgctat gctccgcgcc 360 catcgtctgc accagctggc ctttgacacc taccaggagt ttgaagaagc ctatatccca 420 aaggaacaga agtattcatt cctgcagaac ccccagacct ccctctgttt ctcagagtct 480 attccgacac cctccaacag ggaggaaaca caacagaaat ccaacctaga gctgctccgc 540 atctccctgc tgctcatcca gtcgtggctg gagcccgtgc agttcctcag gagtgtcttc 600 gccaacagcc tggtgtacgg cgcctctgac agcaacgtct atgacctcct aaaggaccta 660 gaggaaggca tccaaacgct gatggggagg ctggaagatg gcagcccccg gactgggcag 720 atcttcaagc agacctacag caagttcgac acaaactcac acaacgatga cgcactactc 780 aagaactacg ggctgctcta ctgcttcagg aaggacatgg acaaggtcga gacattcctg 840 cgcatcgtgc agtgccgctc tgtggagggc agctgtggct tcggcggagg tgggagtgac 900 tactggggcc aaggaaccct ggtcaccgtc tcctcagcca gcactaaagg tccatctgtg 960 ttccctctgg ctccttgcag ccggagcacc tccgagtcca cagccgctct gggatgtctg 1020 gtgaaagatt acttccccga gcccgtcacc gtgagctgga atagcggagc actgacctcc 1080 ggcgtccaca cattccccgc cgtgctccaa agctccggcc tgtacagcct ctcctccgtg 1140 gtcaccgtgc ccagcagctc tctgggcaca aagacctata cctgtaacgt ggatcacaag 1200 cctagcaaca ccaaagtgga taagcgggtg gagagcaagt acggccctcc ctgtccccct 1260 tgccccgctc ctgaggccgc tggcggacct tccgtgttcc tgtttccccc taagcccaag 1320 gacaccctca tgattagccg gacacccgaa gtgacctgcg tggtcgtgga tgtgtcccag 1380 gaggaccctg aagtgcaatt taactggtac gtggacggcg tcgaggtgca caacgccaag 1440 accaagcctc gggaagagca gttcaacagc acctaccggg tggtcagcgt gctgacagtg 1500 ctgcaccagg actggctgaa cggcaaggag tacaagtgca aggtgagcaa caagggcctg 1560 cccagctcca tcgagaagac catcagcaag gccaagggcc agcccaggga accccaggtg 1620 tataccctgc cccctagcca ggaggaaatg accaaaaacc aggtgagcct gacctgcctg 1680 gtgaagggct tctaccccag cgacatcgcc gtggagtggg agagcaacgg ccagcccgag 1740 aacaattaca agaccacccc tcctgtgctg gacagcgacg gctccttctt tctgtatagc 1800 cggctgaccg tggacaagag caggtggcag gagggcaacg tgttctcctg tagcgtgatg 1860 cacgaggccc tgcacaacca ttacacccag aagagcttga gcctgagcct gggcaaa 1917 <210> 107 <211> 1782 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 107 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggtggc 300 ggaggatctg ttccaattca aaaggttcaa gatgatacca aaactctgat taaaactatt 360 gtcacgcgta taaacgacat cagccatacc cagtcggtta gctcaaagca aaaagttacc 420 ggtttggact ttattccggg actgcacccg atcctgaccc ttagtaaaat ggaccagaca 480 ctggccgtct accagcaaat cctgacatcg atgccatcca gaaatgtgat acaaattagc 540 aacgatttgg aaaaccttcg cgatctgctg cacgtgctgg ccttcagtaa gtcctgtcat 600 ctgccgtggg cgtcgggact ggagactctt gactcgctgg gtggagtgtt agaggcctct 660 ggctattcta ctgaagtcgt tgcgctgtca cgcctccagg ggagcctgca ggacatgctg 720 tggcagctgg acctgtcacc tggctgcgga ggtggtggtt cagactactg gggccaagga 780 accctggtca ccgtctcctc agccagcact aaaggtccat ctgtgttccc tctggctcct 840 tgcagccgga gcacctccga gtccacagcc gctctgggat gtctggtgaa agattacttc 900 cccgagcccg tcaccgtgag ctggaatagc ggagcactga cctccggcgt ccacacattc 960 cccgccgtgc tccaaagctc cggcctgtac agcctctcct ccgtggtcac cgtgcccagc 1020 agctctctgg gcacaaagac ctatacctgt aacgtggatc acaagcctag caacaccaaa 1080 gtggataagc gggtggagag caagtacggc cctccctgtc ccccttgccc cgctcctgag 1140 gccgctggcg gaccttccgt gttcctgttt ccccctaagc ccaaggacac cctcatgatt 1200 agccggacac ccgaagtgac ctgcgtggtc gtggatgtgt cccaggagga ccctgaagtg 1260 caatttaact ggtacgtgga cggcgtcgag gtgcacaacg ccaagaccaa gcctcgggaa 1320 gagcagttca acagcaccta ccgggtggtc agcgtgctga cagtgctgca ccaggactgg 1380 ctgaacggca aggagtacaa gtgcaaggtg agcaacaagg gcctgcccag ctccatcgag 1440 aagaccatca gcaaggccaa gggccagccc agggaacccc aggtgtatac cctgccccct 1500 agccaggagg aaatgaccaa aaaccaggtg agcctgacct gcctggtgaa gggcttctac 1560 cccagcgaca tcgccgtgga gtgggagagc aacggccagc ccgagaacaa ttacaagacc 1620 acccctcctg tgctggacag cgacggctcc ttctttctgt atagccggct gaccgtggac 1680 aagagcaggt ggcaggaggg caacgtgttc tcctgtagcg tgatgcacga ggccctgcac 1740 aaccattaca cccagaagag cttgagcctg agcctgggca aa 1782 <210> 108 <211> 1839 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 108 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggtggt 300 ggcggaagct gtgatctgcc tcaaacccac agcctgggta gcaggaggac cttgatgctc 360 ctggcacaga tgaggagaat ctctcttttc tcctgcttga aggacagaca tgactttgga 420 tttccccagg aggagtttgg caaccagttc caaaaggctg aaaccatccc tgtcctccat 480 gagatgatcc agcagatctt caatctcttc agcacaaagg actcatctgc tgcttgggat 540 gagaccctcc tagacaaatt ctacactgaa ctctaccagc agctgaatga cctggaagcc 600 tgtgtgatac agggggtggg ggtgacagag actcccctga tgaaggagga ctccattctg 660 gctgtgagga aatacttcca aagaatcact ctctatctga aagagaagaa atacagccct 720 tgtgcctggg aggttgtcag agcagaaatc atgagatctt tttctttgtc aacaaacttg 780 caagaaagtt taagaagtaa ggaaggcgga ggtgggagtg actactgggg ccaaggaacc 840 ctggtcaccg tctcctcagc cagcactaaa ggtccatctg tgttccctct ggctccttgc 900 agccggagca cctccgagtc cacagccgct ctgggatgtc tggtgaaaga ttacttcccc 960 gagcccgtca ccgtgagctg gaatagcgga gcactgacct ccggcgtcca cacatcccc 1020 gccgtgctcc aaagctccgg cctgtacagc ctctcctccg tggtcaccgt gcccagcagc 1080 tctctgggca caaagaccta tacctgtaac gtggatcaca agcctagcaa caccaaagtg 1140 gataagcggg tggagagcaa gtacggccct ccctgtcccc cttgccccgc tcctgaggcc 1200 gctggcggac cttccgtgtt cctgtttccc cctaagccca aggacaccct catgattagc 1260 cggacacccg aagtgacctg cgtggtcgtg gatgtgtccc aggaggaccc tgaagtgcaa 1320 tttaactggt acgtggacgg cgtcgaggtg cacaacgcca agaccaagcc tcgggaagag 1380 cagttcaaca gcacctaccg ggtggtcagc gtgctgacag tgctgcacca ggactggctg 1440 aacggcaagg agtacaagtg caaggtgagc aacaagggcc tgcccagctc catcgagaag 1500 accatcagca aggccaaggg ccagcccagg gaaccccagg tgtataccct gcccccctagc 1560 caggaggaaa tgaccaaaaa ccaggtgagc ctgacctgcc tggtgaaggg cttctacccc 1620 agcgacatcg ccgtggagtg ggagagcaac ggccagcccg agaacaatta caagaccacc 1680 cctcctgtgc tggacagcga cggctccttc tttctgtata gccggctgac cgtggacaag 1740 agcaggtggc aggagggcaa cgtgttctcc tgtagcgtga tgcacgaggc cctgcacaac 1800 cattacaccc agaagagctt gagcctgagc ctgggcaaa 1839 <210> 109 <211> 1458 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 109 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagatgcggg 300 ggtggcggaa gcatcgaagg tcgtcacgct gagggaacat tcacttccga tgtgtcctcc 360 tacctggagg gccaggctgc caaagagttc atcgcttggc tcgtcaaggg caggggcgga 420 ggtgggagtt gcgactactg gggccaagga accctggtca ccgtctcctc agcctccacc 480 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 540 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 600 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 660 tccctcagca gcgtggtgac tgtgccctct agcagcttgg gcacccagac ctacatctgc 720 aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgaacc caaatcttgc 780 gacaaaactc acacatgccc accgtgccca gcacctccag tcgccggacc gtcagtcttc 840 ctcttccctc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 900 gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 960 gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 1020 gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1080 aaggtctcca acaaaggcct cccaagctcc atcgagaaaa ccatctccaa agccaaaggg 1140 cagccccgag aaccacaggt gtacaccctg cctccatccc gggatgagct gaccaagaac 1200 caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1260 gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1320 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1380 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1440 tccctgtctc cgggtaaa 1458 <210> 110 <211> 1521 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 110 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagggggt 300 ggcggaagcg cgcaagagcc agtcaaaggt ccagtctcca ctaagcctgg ctcctgcccc 360 attatcttga tccggtgcgc catgttgaat ccccctaacc gctgcttgaa agatactgac 420 tgcccaggaa tcaagaagtg ctgtgaaggc tcttgcggga tggcctgttt cgttccccag 480 ggcggaggtg ggagtgacta ctggggccaa ggaaccctgg tcaccgtctc ctcagcctcc 540 accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tggggggcaca 600 gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 660 tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 720 tactccctca gcagcgtggt gactgtgccc tctagcagct tgggcaccca gacctacatc 780 tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agaaagttga acccaaatct 840 tgcgacaaaa ctcacacatg cccaccgtgc ccagcacctc cagtcgccgg accgtcagtc 900 ttcctcttcc ctccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 960 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 1020 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 1080 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1140 tgcaaggtct ccaacaaagg cctcccaagc tccatcgaga aaaccatctc caaagccaaa 1200 gggcagcccc gagaaccaca ggtgtacacc ctgcctccat cccgggatga gctgaccaag 1260 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1320 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1380 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1440 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1500 ctctccctgt ctccgggtaa a 1521 <210> 111 <211> 1518 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 111 gaagtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc ggggggtggc 300 ggaagcctga aatgttacca acatggtaaa gttgtgactt gtcatcgaga tatgaagttt 360 tgctatcata acactggcat gccttttcga aatctcaagc tcatcctaca gggatgttct 420 tcttcgtgca gtgaaacaga aaacaataag tgttgctcaa cagacagatg caacaaaggc 480 ggaggtggga gttggggcca aggaaccctg gtcaccgtct cctcagcctc caccaagggc 540 ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 600 ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 660 ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 720 agcagcgtgg tgactgtgcc ctctagcagc ttgggcaccc agacctacat ctgcaacgtg 780 aatcacaagc ccagcaacac caaggtggac aagaaagttg aacccaaatc ttgcgacaaa 840 actcacacat gcccaccgtg cccagcacct ccagtcgccg gaccgtcagt cttcctcttc 900 cctccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 960 gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 1020 gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc 1080 agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1140 tccaacaaag gcctcccaag ctccatcgag aaaaccatct ccaaagccaa agggcagccc 1200 cgagaaccac aggtgtacac cctgcctcca tcccgggatg agctgaccaa gaaccaggtc 1260 agcctgacct gcctggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1320 aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1380 ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1440 tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 1500 tctccgggta aatgataa 1518 <210> 112 <211> 1552 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 112 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggaggt 300 ggcgggagcg actcttggat ggaagaagtt atcaaactgt gcggtcgtga actggttcgt 360 gctcagatcg ctatctgcgg tatgtctacc tggtctaaac gttctctgtc tcaggaaatc 420 gagggccgta aaaaacgtca gctgtactct gctctggcta acaaatgctg ccacgttggt 480 tgcaccaaac gttctctggc tcgtttctgc ggcggaggtg ggagtgacta ctggggccaa 540 ggaaccctgg tcaccgtctc ctcagcctcc accaagggcc catcggtctt ccccctggca 600 ccctcctcca agagcacctc tgggggcaca gcggccctgg gctgcctggt caaggactac 660 ttccccgaac cggtgacggt gtcgtggaac tcaggcgccc tgaccagcgg cgtgcacacc 720 ttccccggctg tcctacagtc ctcaggactc tactccctca gcagcgtggt gactgtgccc 780 tctagcagct tgggcaccca gacctacatc tgcaacgtga atcacaagcc cagcaacacc 840 aaggtggaca agaaagttga acccaaatct tgcgacaaaa ctcacacatg cccaccgtgc 900 ccagcacctc cagtcgccgg accgtcagtc ttcctcttcc ctccaaaacc caaggacacc 960 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 1020 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1080 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1140 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccaagc 1200 tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 1260 ctgcctccat cccgggatga gctgaccaag aaccaggtca gcctgacctg cctggtcaaa 1320 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1380 tacaagcca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 1440 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 1500 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa at 1552 <210> 113 <211> 1578 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 113 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggaggt 300 ggcgggagcg actcttggat ggaagaagtt atcaaactgt gcggtcgtga actggttcgt 360 gctcagatcg ctatctgcgg tatgtctacc tggtctaaac gttctctgtc tcaggaagac 420 gctccgcaga ccccgcgtcc ggttatcgag ggccgtaaaa aacgtcagct gtactctgct 480 ctggctaaca aatgctgcca cgttggttgc accaaacgtt ctctggctcg tttctgcggc 540 ggaggtggga gtgactactg gggccaagga accctggtca ccgtctcctc agcctccacc 600 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 660 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 720 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 780 tccctcagca gcgtggtgac tgtgccctct agcagcttgg gcacccagac ctacatctgc 840 aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgaacc caaatcttgc 900 gacaaaactc acacatgccc accgtgccca gcacctccag tcgccggacc gtcagtcttc 960 ctcttccctc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 1020 gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 1080 gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 1140 gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1200 aaggtctcca acaaaggcct cccaagctcc atcgagaaaa ccatctccaa agccaaaggg 1260 cagccccgag aaccacaggt gtacaccctg cctccatccc gggatgagct gaccaagaac 1320 caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1380 gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1440 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1500 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1560 tccctgtctc cgggtaaa 1578 <210> 114 <211> 1929 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 114 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagaggtggt 300 ggcggaagct tcccaaccat tcccttatcc aggctttttg acaacgctat gctccgcgcc 360 catcgtctgc accagctggc ctttgacacc taccaggagt ttgaagaagc ctatatccca 420 aaggaacaga agtattcatt cctgcagaac ccccagacct ccctctgttt ctcagagtct 480 attccgacac cctccaacag ggaggaaaca caacagaaat ccaacctaga gctgctccgc 540 atctccctgc tgctcatcca gtcgtggctg gagcccgtgc agttcctcag gagtgtcttc 600 gccaacagcc tggtgtacgg cgcctctgac agcaacgtct atgacctcct aaaggaccta 660 gaggaaggca tccaaacgct gatggggagg ctggaagatg gcagcccccg gactgggcag 720 atcttcaagc agacctacag caagttcgac acaaactcac acaacgatga cgcactactc 780 aagaactacg ggctgctcta ctgcttcagg aaggacatgg acaaggtcga gacattcctg 840 cgcatcgtgc agtgccgctc tgtggagggc agctgtggct tcggcggagg tgggagtgac 900 tactggggcc aaggaaccct ggtcaccgtc tcctcagcct ccaccaaggg cccatcggtc 960 ttccccctgg caccctcctc caagagcacc tctgggggca cagcggccct gggctgcctg 1020 gtcaaggact acttccccga accggtgacg gtgtcgtgga actcaggcgc cctgaccagc 1080 ggcgtgcaca ccttcccggc tgtcctacag tcctcaggac tctactccct cagcagcgtg 1140 gtgactgtgc cctctagcag cttgggcacc cagacctaca tctgcaacgt gaatcacaag 1200 cccagcaaca ccaaggtgga caagaaagtt gaacccaaat cttgcgacaa aactcacaca 1260 tgcccaccgt gcccagcacc tccagtcgcc ggaccgtcag tcttcctctt ccctccaaaa 1320 cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1380 agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1440 gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1500 accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 1560 ggcctcccaa gctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1620 caggtgtaca ccctgcctcc atcccgggat gagctgacca agaaccaggt cagcctgacc 1680 tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1740 ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1800 tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1860 gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1920 aaatgataa 1929 <210> 115 <211> 1855 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 115 gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180 gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240 cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagggtgg 300 tggcggaagc atgagctaca acttgcttgg attcctacaa agaagcagca attttcagtg 360 tcagaagctc ctgtggcaat tgaatgggag gcttgaatac tgcctcaagg acaggatgaa 420 ctttgacatc cctgaggaga ttaagcagct gcagcagttc cagaaggagg acgccgcatt 480 gaccatctat gagatgctcc agaacatctt tgctattttc agacaagatt catctagcac 540 tggctggaat gagactattg ttgagaacct cctggctaat gtctatcatc agataaacca 600 tctgaagaca gtcctggaag aaaaactgga gaaagaagat ttcaccaggg gaaaactcat 660 gagcagtctg cacctgaaaa gatattatgg gaggattctg cattacctga aggccaagga 720 gtacagtcac tgtgcctgga ccatagtcag agtggaaatc ctaaggaact tttacttcat 780 taacagactt acaggttacc tccgaaacgg cggaggtggg agtgactact ggggccaagg 840 aaccctggtc accgtctcct cagcctccac caagggccca tcggtcttcc ccctggcacc 900 ctcctccaag agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt 960 ccccgaaccg gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt 1020 cccggctgtc ctacagtcct caggactcta ctccctcagc agcgtggtga ctgtgccctc 1080 tagcagcttg ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa 1140 ggtggacaag aaagttgaac ccaaatcttg cgacaaaact cacacatgcc caccgtgccc 1200 agcacctcca gtcgccggac cgtcagtctt cctcttccct ccaaaaccca aggacaccct 1260 catgatctcc cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc 1320 tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc 1380 gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca 1440 ggactggctg aatggcaagg agtacaagtg caaggtctcc aacaaaggcc tcccaagctc 1500 catcgagaaa accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct 1560 gcctccatcc cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg 1620 cttctatccc agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta 1680 caagaccacg cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac 1740 cgtggacaag agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc 1800 tctgcacaac cactacacgc agaagagcct ctccctgtct ccgggtaaat gataa 1855 <210> 116 <211> 1539 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 116 caggtgaccc tgcgcgagtc cggccctgca ctggtgaagc ccacccagac cctgaccctg 60 acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgg 120 cagcctcccg gcaaggccct ggagtggctg gctgacatct ggtgggacga caagaaggac 180 tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240 gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgctct 300 gggggtggcg gaagcctgaa atgttaccaa catggtaaag ttgtgacttg tcatcgagat 360 atgaagtttt gctatcataa cactggcatg ccttttcgaa atctcaagct catcctacag 420 ggatgttctt cttcgtgcag tgaaacagaa aacaataagt gttgctcaac agacagatgc 480 aacaaaggcg gaggtgggag ttactttgac gtgtggggag ccggtaccac cgtgaccgtg 540 tcttccgcct ccaccaaggg cccatcggtc ttccccctgg caccctcctc caagagcacc 600 tctgggggca cagcggccct gggctgcctg gtcaaggact acttccccga accggtgacg 660 gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 720 tcctcaggac tctactccct cagcagcgtg gtgactgtgc cctctagcag cttgggcacc 780 cagacctaca tctgcaacgt gaatcacaag cccagcaaca ccaaggtgga caagaaagtt 840 gaacccaaat cttgcgacaa aactcacaca tgcccaccgt gcccagcacc tccagtcgcc 900 ggaccgtcag tcttcctctt ccctccaaaa cccaaggaca ccctcatgat ctccccggacc 960 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 1020 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 1080 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1140 aaggagtaca agtgcaaggt ctccaacaaa ggcctcccaa gctccatcga gaaaaccatc 1200 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgcctcc atcccgggat 1260 gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1320 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1380 gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1440 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1500 acgcagaaga gcctctccct gtctccgggt aaatgataa 1539 <210> 117 <211> 1911 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 117 caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60 acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120 ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180 cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcggggg tggcggaagc 300 gggggtggcg gaagcgctcc tctgggcggt cctgaaccag cacagtacga ggaactgaca 360 ctgttgttcc atggagcctt gcagctgggc caggccctca acggcgtgta ccgcgccaca 420 gaggcacgtt tgaccgaggc cggacacagc ctgggtttgt acgacagagc cctggagttt 480 ctgggtaccg aagtgcgtca gggccaggac gcaactcagg agctgagaac ctccctctct 540 gagatccagg tggaggagga cgccctgcac ctgcgcgccg aggcgacagc acgctctttg 600 ggagaagttg ctcgcgctca gcaggccctg cgtgataccg tgcggagact ccaagttcag 660 ctcagaggcg cttggctcgg acaggcgcat caggagttcg agaccctgaa agctcgtgcc 720 gacaaacagt cccacctgct gtgggcgctc accggtcacg tccagcgcca gcaacgcgaa 780 atggccgagc agcagcaatg gctgcgccaa atccagcagc gcctgcatac cgcggccctg 840 ccagcgtaag gcggaggtgg gagtggcgga ggtgggagtc atgtggatgt ctggggacag 900 ggcctgctgg tgacagtctc tagtgcttcc acaactgcac caaaggtgta ccccctgtca 960 agctgctgtg gggacaaatc ctctagtacc gtgacactgg gatgcctggt ctcaagctat 1020 atgcccgagc ctgtgactgt cacctggaac tcaggagccc tgaaaagcgg agtgcacacc 1080 ttcccagctg tgctgcagtc ctctggcctg tatagcctga gttcaatggt gacagtcccc 1140 ggcagtactt cagggcagac cttcacctgt aatgtggccc atcctgccag ctccaccaaa 1200 gtggacaaag cagtggaacc caaatcttgc gacaaaactc acacatgccc accgtgccca 1260 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 1320 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 1380 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1440 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1500 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1560 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 1620 ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgacctg cctggtcaaa 1680 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1740 tacaagcca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 1800 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 1860 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 1911 <210> 118 <211> 1881 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 118 caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60 acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120 ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180 cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcggggg tggcggaagc 300 gctcctctgg gcggtcctga accagcacag tacgaggaac tgacactgtt gttccatgga 360 gccttgcagc tgggccaggc cctcaacggc gtgtaccgcg ccacagaggc acgtttgacc 420 gaggccggac acagcctggg tttgtacgac agagccctgg agtttctggg taccgaagtg 480 cgtcagggcc aggacgcaac tcaggagctg agaacctccc tctctgagat ccaggtggag 540 gaggacgccc tgcacctgcg cgccgaggcg acagcacgct ctttgggaga agttgctcgc 600 gctcagcagg ccctgcgtga taccgtgcgg agactccaag ttcagctcag aggcgcttgg 660 ctcggacagg cgcatcagga gttcgagacc ctgaaagctc gtgccgacaa acagtcccac 720 ctgctgtggg cgctcaccgg tcacgtccag cgccagcaac gcgaaatggc cgagcagcag 780 caatggctgc gccaaatcca gcagcgcctg cataccgcgg ccctgccagc gtaaggcgga 840 ggtgggagtc atgtggatgt ctggggacag ggcctgctgg tgacagtctc tagtgcttcc 900 acaactgcac caaaggtgta ccccctgtca agctgctgtg gggacaaatc ctctagtacc 960 gtgacactgg gatgcctggt ctcaagctat atgcccgagc ctgtgactgt cacctggaac 1020 tcaggagccc tgaaaagcgg agtgcacacc ttcccagctg tgctgcagtc ctctggcctg 1080 tatagcctga gttcaatggt gacagtcccc ggcagtactt cagggcagac cttcacctgt 1140 aatgtggccc atcctgccag ctccaccaaa gtggacaaag cagtggaacc caaatcttgc 1200 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 1260 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 1320 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 1380 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 1440 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1500 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1560 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 1620 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1680 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1740 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1800 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1860 ctctccctgt ctccgggtaa a 1881 <210> 119 <211> 1920 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 119 caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60 acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120 ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180 cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcggggg tggcggaagc 300 ttcccaacca ttcccttatc caggcttttt gacaacgcta tgctccgcgc ccatcgtctg 360 caccagctgg cctttgacac ctaccaggag tttgaagaag cctatatccc aaaggaacag 420 aagtattcat tcctgcagaa cccccagacc tccctctgtt tctcagagtc tattccgaca 480 ccctccaaca gggaggaaac acaacagaaa tccaacctag agctgctccg catctccctg 540 ctgctcatcc agtcgtggct ggagcccgtg cagttcctca ggagtgtctt cgccaacagc 600 ctggtgtacg gcgcctctga cagcaacgtc tatgacctcc taaaggacct agaggaaggc 660 atccaaacgc tgatggggag gctggaagat ggcagccccc ggactgggca gatcttcaag 720 cagacctaca gcaagttcga cacaaactca cacaacgatg acgcactact caagaactac 780 gggctgctct actgcttcag gaaggacatg gacaaggtcg agacattcct gcgcatcgtg 840 cagtgccgct ctgtggaggg cagctgtggc ttcggcggag gtgggagtca tgtggatgtc 900 tggggacagg gcctgctggt gacagtctct agtgcttcca caactgcacc aaaggtgtac 960 cccctgtcaa gctgctgtgg ggacaaatcc tctagtaccg tgacactggg atgcctggtc 1020 tcaagctata tgcccgagcc tgtgactgtc acctggaact caggagccct gaaaagcgga 1080 gtgcacacct tcccagctgt gctgcagtcc tctggcctgt atagcctgag ttcaatggtg 1140 acagtccccg gcagtacttc agggcagacc ttcacctgta atgtggccca tcctgccagc 1200 tccaccaaag tggacaaagc agtggaaccc aaatcttgcg acaaaactca cacatgccca 1260 ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 1320 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 1380 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 1440 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1500 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 1560 ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1620 gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 1680 ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1740 gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1800 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1860 atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1920 <210> 120 <211> 1845 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 120 caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60 acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120 ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180 cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcggggg tggcggaagc 300 atgagctaca acttgcttgg attcctacaa agaagcagca attttcagtg tcagaagctc 360 ctgtggcaat tgaatgggag gcttgaatac tgcctcaagg acaggatgaa ctttgacatc 420 cctgaggaga ttaagcagct gcagcagttc cagaaggagg acgccgcatt gaccatctat 480 gagatgctcc agaacatctt tgctattttc agacaagatt catctagcac tggctggaat 540 gagactattg ttgagaacct cctggctaat gtctatcatc agataaacca tctgaagaca 600 gtcctggaag aaaaactgga gaaagaagat ttcaccaggg gaaaactcat gagcagtctg 660 cacctgaaaa gatattatgg gaggattctg cattacctga aggccaagga gtacagtcac 720 tgtgcctgga ccatagtcag agtggaaatc ctaaggaact tttacttcat taacagactt 780 acaggttacc tccgaaacgg cggaggtggg agtcatgtgg atgtctgggg acagggcctg 840 ctggtgacag tctctagtgc ttccacaact gcaccaaagg tgtaccccct gtcaagctgc 900 tgtggggaca aatcctctag taccgtgaca ctgggatgcc tggtctcaag ctatatgccc 960 gagcctgtga ctgtcacctg gaactcagga gccctgaaaa gcggagtgca caccttccca 1020 gctgtgctgc agtcctctgg cctgtatagc ctgagttcaa tggtgacagt ccccggcagt 1080 acttcagggc agaccttcac ctgtaatgtg gcccatcctg ccagctccac caaagtggac 1140 aaagcagtgg aacccaaatc ttgcgacaaa actcacacat gcccaccgtg cccagcacct 1200 gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 1260 atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 1320 gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1380 gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1440 tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1500 gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1560 ccatccccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1620 tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1680 accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1740 gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1800 cacaaccact acaccgcagaa gagcctctcc ctgtctccgg gtaaa 1845 <210> 121 <211> 1944 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 121 caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60 acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120 ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180 cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300 ggaggtggcg gaagcttccc aaccattccc ttatccaggc tttttgacaa cgctatgctc 360 cgcgcccatc gtctgcacca gctggccttt gacacctacc aggagtttga agaagcctat 420 atcccaaagg aacagaagta ttcattcctg cagaaccccc agacctccct ctgtttctca 480 gagtctattc cgacaccctc caacagggag gaaacacaac agaaatccaa cctagagctg 540 ctccgcatct ccctgctgct catccagtcg tggctggagc ccgtgcagtt cctcaggagt 600 gtcttcgcca acagcctggt gtacggcgcc tctgacagca acgtctatga cctcctaaag 660 gacctagagg aaggcatcca aacgctgatg gggaggctgg aagatggcag cccccggact 720 gggcagatct tcaagcagac ctacagcaag ttcgacacaa actcacacaa cgatgacgca 780 ctactcaaga actacgggct gctctactgc ttcaggaagg acatggacaa ggtcgagaca 840 ttcctgcgca tcgtgcagtg ccgctctgtg gagggcagct gtggcttcgg cggaggtggg 900 agttggcatg tggatgtctg gggacagggc ctgctggtga cagtctctag tgcttccaca 960 actgcaccaa aggtgtaccc cctgtcaagc tgctgtgggg acaaatcctc tagtaccgtg 1020 acactgggat gcctggtctc aagctatatg cccgagcctg tgactgtcac ctggaactca 1080 ggagccctga aaagcggagt gcacaccttc ccagctgtgc tgcagtcctc tggcctgtat 1140 agcctgagtt caatggtgac agtccccggc agtacttcag ggcagacctt cacctgtaat 1200 gtggcccatc ctgccagctc caccaaagtg gacaaagcag tggaacccaa atcttgcgac 1260 aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 1320 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 1380 gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 1440 gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 1500 gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1560 aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1620 cagccccgag aaccacaggt gtacaccctg cccccatccc gggatgagct gaccaagaac 1680 caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1740 gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1800 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1860 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1920 tccctgtctc cgggtaaatg ataa 1944 <210> 122 <211> 387 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 122 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Gly Gly Gly Ser 20 25 30 Ala Pro Pro Arg Leu Ile Cys Asp Ser Arg Val Leu Glu Arg Tyr Leu 35 40 45 Leu Glu Ala Lys Glu Ala Glu Asn Ile Thr Thr Gly Cys Ala Glu His 50 55 60 Cys Ser Leu Asn Glu Asn Ile Thr Val Pro Asp Thr Lys Val Asn Phe 65 70 75 80 Tyr Ala Trp Lys Arg Met Glu Val Gly Gln Gln Ala Val Glu Val Trp 85 90 95 Gln Gly Leu Ala Leu Leu Ser Glu Ala Val Leu Arg Gly Gln Ala Leu 100 105 110 Leu Val Asn Ser Ser Gln Pro Trp Glu Pro Leu Gln Leu His Val Asp 115 120 125 Lys Ala Val Ser Gly Leu Arg Ser Leu Thr Thr Leu Leu Arg Ala Leu 130 135 140 Gly Ala Gln Lys Glu Ala Ile Ser Pro Pro Asp Ala Ala Ser Ala Ala 145 150 155 160 Pro Leu Arg Thr Ile Thr Ala Asp Thr Phe Arg Lys Leu Phe Arg Val 165 170 175 Tyr Ser Asn Phe Leu Arg Gly Lys Leu Lys Leu Tyr Thr Gly Glu Ala 180 185 190 Cys Arg Thr Gly Asp Arg Gly Gly Gly Gly Ser Thr Ala Val Ala Trp 195 200 205 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala 210 215 220 Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser 225 230 235 240 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 245 250 255 Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly 260 265 270 Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 275 280 285 Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser 290 295 300 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 305 310 315 320 Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 325 330 335 Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 340 345 350 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 355 360 365 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 370 375 380 Gly Glu Cys 385 <210> 123 <211> 634 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 123 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Gly Gly Gly Ser Thr Pro Leu Gly Pro 100 105 110 Ala Arg Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val 115 120 125 Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu Gln Glu Arg Leu Cys Ala 130 135 140 Ala His Lys Leu Cys His Pro Glu Glu Leu Met Leu Leu Arg His Ser 145 150 155 160 Leu Gly Ile Pro Gln Ala Pro Leu Ser Ser Cys Ser Ser Gln Ser Leu 165 170 175 Gln Leu Thr Ser Cys Leu Asn Gln Leu His Gly Gly Leu Phe Leu Tyr 180 185 190 Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile Ser Pro Glu Leu Ala Pro 195 200 205 Thr Leu Asp Thr Leu Gln Leu Asp Val Thr Asp Phe Ala Thr Asn Ile 210 215 220 Trp Leu Gln Met Glu Asp Leu Gly Ala Ala Pro Ala Val Gln Pro Thr 225 230 235 240 Gln Gly Ala Met Pro Thr Phe Thr Ser Ala Phe Gln Arg Arg Ala Gly 245 250 255 Gly Val Leu Val Ala Ser Gln Leu His Arg Phe Leu Glu Leu Ala Tyr 260 265 270 Arg Gly Leu Arg Tyr Leu Ala Glu Pro Gly Gly Gly Gly Ser Gly Phe 275 280 285 Tyr Ala Met Asp Tyr Trp Gly Gly Gly Thr Leu Val Thr Val Ser Ser 290 295 300 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 305 310 315 320 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 325 330 335 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 340 345 350 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 355 360 365 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 370 375 380 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 385 390 395 400 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 405 410 415 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 420 425 430 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 435 440 445 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 450 455 460 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 465 470 475 480 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 485 490 495 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 500 505 510 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 515 520 525 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 530 535 540 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 545 550 555 560 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 565 570 575 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 580 585 590 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 595 600 605 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 610 615 620 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 625 630 <210> 124 <211> 496 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 124 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Cys Gly Gly Gly Gly Ser Ile Glu Gly Arg His Gly Glu Gly 100 105 110 Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg 115 120 125 Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro 130 135 140 Pro Pro Ser Gly Gly Gly Gly Ser Cys Asp Tyr Trp Gly Gln Gly Thr 145 150 155 160 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 165 170 175 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 180 185 190 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 195 200 205 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 210 215 220 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 225 230 235 240 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 245 250 255 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 260 265 270 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 275 280 285 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 290 295 300 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 305 310 315 320 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 325 330 335 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 340 345 350 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 355 360 365 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 370 375 380 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 385 390 395 400 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 405 410 415 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 420 425 430 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 435 440 445 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 450 455 460 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 465 470 475 480 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 495 <210> 125 <211> 485 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 125 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Ile Asn Val Lys Cys Ser Leu Pro Gln 100 105 110 Gln Cys Ile Lys Pro Cys Lys Asp Ala Gly Met Arg Phe Gly Lys Cys 115 120 125 Met Asn Lys Lys Cys Arg Cys Tyr Ser Gly Gly Gly Gly Ser Asp Tyr 130 135 140 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 145 150 155 160 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 165 170 175 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 180 185 190 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 195 200 205 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 210 215 220 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 225 230 235 240 Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 245 250 255 Ser Cys Asp Lys Thr His Thr Cys Pro Cys Pro Ala Pro Glu Leu 260 265 270 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 275 280 285 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 290 295 300 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 305 310 315 320 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 325 330 335 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 340 345 350 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 355 360 365 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 370 375 380 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 385 390 395 400 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 405 410 415 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 420 425 430 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 435 440 445 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 450 455 460 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 465 470 475 480 Leu Ser Pro Gly Lys 485 <210> 126 <211> 487 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 126 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Ala Ala Ala Ile Ser Cys Val Gly Ser 100 105 110 Pro Glu Cys Pro Pro Lys Cys Arg Ala Gln Gly Cys Lys Asn Gly Lys 115 120 125 Cys Met Asn Arg Lys Cys Lys Cys Tyr Tyr Cys Gly Gly Gly Gly Ser 130 135 140 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 145 150 155 160 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 165 170 175 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 180 185 190 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 195 200 205 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 210 215 220 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 225 230 235 240 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 245 250 255 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 260 265 270 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Lys Pro Lys 275 280 285 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 290 295 300 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 305 310 315 320 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 325 330 335 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 340 345 350 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 355 360 365 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 370 375 380 Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys 385 390 395 400 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 405 410 415 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 420 425 430 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 435 440 445 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 450 455 460 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 465 470 475 480 Leu Ser Leu Ser Pro Gly Lys 485 <210> 127 <211> 626 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 127 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Ala Thr Pro Leu Gly Pro Ala Ser Ser 100 105 110 Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val Arg Lys Ile 115 120 125 Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Val Ser Glu Cys Ala 130 135 140 Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser 145 150 155 160 Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu 165 170 175 Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr 180 185 190 Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro 195 200 205 Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile 210 215 220 Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro Thr 225 230 235 240 Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly 245 250 255 Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr 260 265 270 Arg Val Leu Arg His Leu Ala Gln Pro Gly Gly Gly Gly Ser Asp Tyr 275 280 285 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 290 295 300 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 305 310 315 320 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 325 330 335 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 340 345 350 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 355 360 365 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 370 375 380 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 385 390 395 400 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 405 410 415 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 420 425 430 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 435 440 445 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 450 455 460 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 465 470 475 480 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 485 490 495 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 500 505 510 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 515 520 525 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 530 535 540 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 545 550 555 560 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 565 570 575 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp 580 585 590 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 595 600 605 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 610 615 620 Gly Lys 625 <210> 128 <211> 639 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 128 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Phe Pro Thr Ile Pro Leu Ser Arg Leu 100 105 110 Phe Asp Asn Ala Met Leu Arg Ala His Arg Leu His Gln Leu Ala Phe 115 120 125 Asp Thr Tyr Gln Glu Phe Glu Glu Ala Tyr Ile Pro Lys Glu Gln Lys 130 135 140 Tyr Ser Phe Leu Gln Asn Pro Gln Thr Ser Leu Cys Phe Ser Glu Ser 145 150 155 160 Ile Pro Thr Pro Ser Asn Arg Glu Glu Thr Gln Gln Lys Ser Asn Leu 165 170 175 Glu Leu Leu Arg Ile Ser Leu Leu Leu Ile Gln Ser Trp Leu Glu Pro 180 185 190 Val Gln Phe Leu Arg Ser Val Phe Ala Asn Ser Leu Val Tyr Gly Ala 195 200 205 Ser Asp Ser Asn Val Tyr Asp Leu Leu Lys Asp Leu Glu Glu Gly Ile 210 215 220 Gln Thr Leu Met Gly Arg Leu Glu Asp Gly Ser Pro Arg Thr Gly Gln 225 230 235 240 Ile Phe Lys Gln Thr Tyr Ser Lys Phe Asp Thr Asn Ser His Asn Asp 245 250 255 Asp Ala Leu Leu Lys Asn Tyr Gly Leu Leu Tyr Cys Phe Arg Lys Asp 260 265 270 Met Asp Lys Val Glu Thr Phe Leu Arg Ile Val Gln Cys Arg Ser Val 275 280 285 Glu Gly Ser Cys Gly Phe Gly Gly Gly Gly Ser Asp Tyr Trp Gly Gln 290 295 300 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 305 310 315 320 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 325 330 335 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 340 345 350 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 355 360 365 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 370 375 380 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 385 390 395 400 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 405 410 415 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 420 425 430 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 435 440 445 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 450 455 460 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 465 470 475 480 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 485 490 495 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 500 505 510 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 515 520 525 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 530 535 540 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 545 550 555 560 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 565 570 575 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 580 585 590 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 595 600 605 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 610 615 620 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 625 630 635 <210> 129 <211> 594 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 129 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Gly Ser Val Pro Ile Gln Lys Val Gln Asp Asp 100 105 110 Thr Lys Thr Leu Ile Lys Thr Ile Val Thr Arg Ile Asn Asp Ile Ser 115 120 125 His Thr Gln Ser Val Ser Ser Lys Gln Lys Val Thr Gly Leu Asp Phe 130 135 140 Ile Pro Gly Leu His Pro Ile Leu Thr Leu Ser Lys Met Asp Gln Thr 145 150 155 160 Leu Ala Val Tyr Gln Gln Ile Leu Thr Ser Met Pro Ser Arg Asn Val 165 170 175 Ile Gln Ile Ser Asn Asp Leu Glu Asn Leu Arg Asp Leu Leu His Val 180 185 190 Leu Ala Phe Ser Lys Ser Cys His Leu Pro Trp Ala Ser Gly Leu Glu 195 200 205 Thr Leu Asp Ser Leu Gly Gly Val Leu Glu Ala Ser Gly Tyr Ser Thr 210 215 220 Glu Val Val Ala Leu Ser Arg Leu Gln Gly Ser Leu Gln Asp Met Leu 225 230 235 240 Trp Gln Leu Asp Leu Ser Pro Gly Cys Gly Gly Gly Gly Gly Ser Asp Tyr 245 250 255 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 260 265 270 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 275 280 285 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 290 295 300 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 305 310 315 320 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 325 330 335 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 340 345 350 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 355 360 365 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 370 375 380 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 385 390 395 400 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 405 410 415 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 420 425 430 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 435 440 445 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 450 455 460 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 465 470 475 480 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 485 490 495 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 500 505 510 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 515 520 525 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 530 535 540 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp 545 550 555 560 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 565 570 575 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 580 585 590 Gly Lys <210> 130 <211> 613 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 130 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Cys Asp Leu Pro Gln Thr His Ser Leu 100 105 110 Gly Ser Arg Arg Thr Leu Met Leu Leu Ala Gln Met Arg Arg Ile Ser 115 120 125 Leu Phe Ser Cys Leu Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu 130 135 140 Glu Phe Gly Asn Gln Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His 145 150 155 160 Glu Met Ile Gln Gln Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser 165 170 175 Ala Ala Trp Asp Glu Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr 180 185 190 Gln Gln Leu Asn Asp Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val 195 200 205 Thr Glu Thr Pro Leu Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys 210 215 220 Tyr Phe Gln Arg Ile Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro 225 230 235 240 Cys Ala Trp Glu Val Val Arg Ala Glu Ile Met Arg Ser Phe Ser Leu 245 250 255 Ser Thr Asn Leu Gln Glu Ser Leu Arg Ser Lys Glu Gly Gly Gly Gly 260 265 270 Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 275 280 285 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr 290 295 300 Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 305 310 315 320 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 325 330 335 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 340 345 350 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr 355 360 365 Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 370 375 380 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala 385 390 395 400 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 405 410 415 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 420 425 430 Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 435 440 445 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 450 455 460 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 465 470 475 480 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 485 490 495 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 500 505 510 Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 515 520 525 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 530 535 540 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 545 550 555 560 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 565 570 575 Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 580 585 590 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 595 600 605 Leu Ser Leu Gly Lys 610 <210> 131 <211> 486 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 131 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Cys Gly Gly Gly Gly Ser Ile Glu Gly Arg His Ala Glu Gly 100 105 110 Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys 115 120 125 Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly Gly Gly Ser Cys 130 135 140 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 145 150 155 160 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 165 170 175 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 180 185 190 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 195 200 205 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 210 215 220 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 225 230 235 240 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 245 250 255 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 260 265 270 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Lys Pro Lys Asp 275 280 285 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 290 295 300 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 305 310 315 320 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 325 330 335 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 340 345 350 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 355 360 365 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 370 375 380 Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn 385 390 395 400 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 405 410 415 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 420 425 430 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 435 440 445 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 450 455 460 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 465 470 475 480 Ser Leu Ser Pro Gly Lys 485 <210> 132 <211> 507 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 132 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Ala Gln Glu Pro Val Lys Gly Pro Val 100 105 110 Ser Thr Lys Pro Gly Ser Cys Pro Ile Ile Leu Ile Arg Cys Ala Met 115 120 125 Leu Asn Pro Pro Asn Arg Cys Leu Lys Asp Thr Asp Cys Pro Gly Ile 130 135 140 Lys Lys Cys Cys Glu Gly Ser Cys Gly Met Ala Cys Phe Val Pro Gln 145 150 155 160 Gly Gly Gly Gly Ser Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 165 170 175 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 180 185 190 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 195 200 205 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 210 215 220 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 225 230 235 240 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 245 250 255 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 260 265 270 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 275 280 285 Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro 290 295 300 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 305 310 315 320 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 325 330 335 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 340 345 350 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 355 360 365 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 370 375 380 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 385 390 395 400 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 405 410 415 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 420 425 430 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 435 440 445 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 450 455 460 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 465 470 475 480 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 485 490 495 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 500 505 <210> 133 <211> 504 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 133 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Gly Gly Gly Gly Ser Leu Lys Cys Tyr Gln His Gly Lys Val Val 100 105 110 Thr Cys His Arg Asp Met Lys Phe Cys Tyr His Asn Thr Gly Met Pro 115 120 125 Phe Arg Asn Leu Lys Leu Ile Leu Gln Gly Cys Ser Ser Ser Cys Ser 130 135 140 Glu Thr Glu Asn Asn Lys Cys Cys Ser Thr Asp Arg Cys Asn Lys Gly 145 150 155 160 Gly Gly Gly Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 165 170 175 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 180 185 190 Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 195 200 205 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 210 215 220 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 225 230 235 240 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 245 250 255 Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys 260 265 270 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 275 280 285 Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 290 295 300 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 305 310 315 320 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 325 330 335 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 340 345 350 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 355 360 365 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 370 375 380 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 385 390 395 400 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 405 410 415 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 420 425 430 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 435 440 445 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 450 455 460 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 465 470 475 480 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 485 490 495 Ser Leu Ser Leu Ser Pro Gly Lys 500 <210> 134 <211> 517 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 134 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Asp Ser Trp Met Glu Glu Val Ile Lys 100 105 110 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 115 120 125 Ser Thr Trp Ser Lys Arg Ser Leu Ser Gln Glu Ile Glu Gly Arg Lys 130 135 140 Lys Arg Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly 145 150 155 160 Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys Gly Gly Gly Gly Ser Asp 165 170 175 Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 180 185 190 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 195 200 205 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 210 215 220 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 225 230 235 240 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 245 250 255 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 260 265 270 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 275 280 285 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro 290 295 300 Val Ala Gly Pro Ser Val Phe Leu Phe Pro Lys Pro Lys Asp Thr 305 310 315 320 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 325 330 335 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 340 345 350 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 355 360 365 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 370 375 380 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 385 390 395 400 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 405 410 415 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 420 425 430 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 435 440 445 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 450 455 460 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 465 470 475 480 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 485 490 495 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 500 505 510 Leu Ser Pro Gly Lys 515 <210> 135 <211> 526 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 135 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Asp Ser Trp Met Glu Glu Val Ile Lys 100 105 110 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 115 120 125 Ser Thr Trp Ser Lys Arg Ser Leu Ser Gln Glu Asp Ala Pro Gln Thr 130 135 140 Pro Arg Pro Val Ile Glu Gly Arg Lys Lys Arg Gln Leu Tyr Ser Ala 145 150 155 160 Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala 165 170 175 Arg Phe Cys Gly Gly Gly Gly Ser Asp Tyr Trp Gly Gln Gly Thr Leu 180 185 190 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 195 200 205 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 210 215 220 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 225 230 235 240 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 245 250 255 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 260 265 270 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 275 280 285 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 290 295 300 Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 305 310 315 320 Leu Phe Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 325 330 335 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 340 345 350 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 355 360 365 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 370 375 380 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 385 390 395 400 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 405 410 415 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 420 425 430 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 435 440 445 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 450 455 460 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Val Leu Asp Ser Asp 465 470 475 480 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 485 490 495 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 500 505 510 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 515 520 525 <210> 136 <211> 641 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 136 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Phe Pro Thr Ile Pro Leu Ser Arg Leu 100 105 110 Phe Asp Asn Ala Met Leu Arg Ala His Arg Leu His Gln Leu Ala Phe 115 120 125 Asp Thr Tyr Gln Glu Phe Glu Glu Ala Tyr Ile Pro Lys Glu Gln Lys 130 135 140 Tyr Ser Phe Leu Gln Asn Pro Gln Thr Ser Leu Cys Phe Ser Glu Ser 145 150 155 160 Ile Pro Thr Pro Ser Asn Arg Glu Glu Thr Gln Gln Lys Ser Asn Leu 165 170 175 Glu Leu Leu Arg Ile Ser Leu Leu Leu Ile Gln Ser Trp Leu Glu Pro 180 185 190 Val Gln Phe Leu Arg Ser Val Phe Ala Asn Ser Leu Val Tyr Gly Ala 195 200 205 Ser Asp Ser Asn Val Tyr Asp Leu Leu Lys Asp Leu Glu Glu Gly Ile 210 215 220 Gln Thr Leu Met Gly Arg Leu Glu Asp Gly Ser Pro Arg Thr Gly Gln 225 230 235 240 Ile Phe Lys Gln Thr Tyr Ser Lys Phe Asp Thr Asn Ser His Asn Asp 245 250 255 Asp Ala Leu Leu Lys Asn Tyr Gly Leu Leu Tyr Cys Phe Arg Lys Asp 260 265 270 Met Asp Lys Val Glu Thr Phe Leu Arg Ile Val Gln Cys Arg Ser Val 275 280 285 Glu Gly Ser Cys Gly Phe Gly Gly Gly Gly Ser Asp Tyr Trp Gly Gln 290 295 300 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 305 310 315 320 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 325 330 335 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 340 345 350 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 355 360 365 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 370 375 380 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 385 390 395 400 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 405 410 415 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 420 425 430 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 435 440 445 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 450 455 460 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 465 470 475 480 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 485 490 495 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 500 505 510 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 515 520 525 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 530 535 540 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 545 550 555 560 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 565 570 575 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 580 585 590 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 595 600 605 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 610 615 620 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 625 630 635 640 Lys <210> 137 <211> 616 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 137 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Gly Ser Met Ser Tyr Asn Leu Leu Gly Phe Leu 100 105 110 Gln Arg Ser Ser Asn Phe Gln Cys Gln Lys Leu Leu Trp Gln Leu Asn 115 120 125 Gly Arg Leu Glu Tyr Cys Leu Lys Asp Arg Met Asn Phe Asp Ile Pro 130 135 140 Glu Glu Ile Lys Gln Leu Gln Gln Phe Gln Lys Glu Asp Ala Ala Leu 145 150 155 160 Thr Ile Tyr Glu Met Leu Gln Asn Ile Phe Ala Ile Phe Arg Gln Asp 165 170 175 Ser Ser Ser Thr Gly Trp Asn Glu Thr Ile Val Glu Asn Leu Leu Ala 180 185 190 Asn Val Tyr His Gln Ile Asn His Leu Lys Thr Val Leu Glu Glu Lys 195 200 205 Leu Glu Lys Glu Asp Phe Thr Arg Gly Lys Leu Met Ser Ser Leu His 210 215 220 Leu Lys Arg Tyr Tyr Gly Arg Ile Leu His Tyr Leu Lys Ala Lys Glu 225 230 235 240 Tyr Ser His Cys Ala Trp Thr Ile Val Arg Val Glu Ile Leu Arg Asn 245 250 255 Phe Tyr Phe Ile Asn Arg Leu Thr Gly Tyr Leu Arg Asn Gly Gly Gly 260 265 270 Gly Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 275 280 285 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 290 295 300 Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 305 310 315 320 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 325 330 335 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 340 345 350 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 355 360 365 Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys 370 375 380 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 385 390 395 400 Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 405 410 415 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 420 425 430 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 435 440 445 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 450 455 460 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 465 470 475 480 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 485 490 495 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 500 505 510 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 515 520 525 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 530 535 540 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 545 550 555 560 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 565 570 575 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 580 585 590 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 595 600 605 Ser Leu Ser Leu Ser Pro Gly Lys 610 615 <210> 138 <211> 511 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 138 Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Gly Gly Gly Gly Ser Leu Lys Cys Tyr Gln His Gly 100 105 110 Lys Val Val Thr Cys His Arg Asp Met Lys Phe Cys Tyr His Asn Thr 115 120 125 Gly Met Pro Phe Arg Asn Leu Lys Leu Ile Leu Gln Gly Cys Ser Ser 130 135 140 Ser Cys Ser Glu Thr Glu Asn Asn Lys Cys Cys Ser Thr Asp Arg Cys 145 150 155 160 Asn Lys Gly Gly Gly Gly Ser Tyr Phe Asp Val Trp Gly Ala Gly Thr 165 170 175 Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 180 185 190 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 195 200 205 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 210 215 220 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 225 230 235 240 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 245 250 255 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 260 265 270 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 275 280 285 His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 290 295 300 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 305 310 315 320 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 325 330 335 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 340 345 350 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 355 360 365 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 370 375 380 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 385 390 395 400 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 405 410 415 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 420 425 430 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 435 440 445 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 450 455 460 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 465 470 475 480 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 485 490 495 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 500 505 510 <210> 139 <211> 642 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 139 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro 100 105 110 Leu Gly Gly Pro Glu Pro Ala Gln Tyr Glu Glu Leu Thr Leu Leu Phe 115 120 125 His Gly Ala Leu Gln Leu Gly Gln Ala Leu Asn Gly Val Tyr Arg Ala 130 135 140 Thr Glu Ala Arg Leu Thr Glu Ala Gly His Ser Leu Gly Leu Tyr Asp 145 150 155 160 Arg Ala Leu Glu Phe Leu Gly Thr Glu Val Arg Gln Gly Gln Asp Ala 165 170 175 Thr Gln Glu Leu Arg Thr Ser Leu Ser Glu Ile Gln Val Glu Glu Asp 180 185 190 Ala Leu His Leu Arg Ala Glu Ala Thr Ala Arg Ser Leu Gly Glu Val 195 200 205 Ala Arg Ala Gln Gln Ala Leu Arg Asp Thr Val Arg Arg Leu Gln Val 210 215 220 Gln Leu Arg Gly Ala Trp Leu Gly Gln Ala His Gln Glu Phe Glu Thr 225 230 235 240 Leu Lys Ala Arg Ala Asp Lys Gln Ser His Leu Leu Trp Ala Leu Thr 245 250 255 Gly His Val Gln Arg Gln Gln Arg Glu Met Ala Glu Gln Gln Gln Trp 260 265 270 Leu Arg Gln Ile Gln Gln Arg Leu His Thr Ala Ala Leu Pro Ala Gly 275 280 285 Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Trp His Val Asp Val Trp Gly 290 295 300 Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys 305 310 315 320 Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val 325 330 335 Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val 340 345 350 Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala 355 360 365 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val 370 375 380 Pro Gly Ser Thr Ser Gly Gin Thr Phe Thr Cys Asn Val Ala His Pro 385 390 395 400 Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp 405 410 415 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 420 425 430 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 435 440 445 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 450 455 460 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 465 470 475 480 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 485 490 495 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 500 505 510 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 515 520 525 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 530 535 540 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 545 550 555 560 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 565 570 575 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 580 585 590 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 595 600 605 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 610 615 620 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 625 630 635 640 Gly Lys <210> 140 <211> 632 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 140 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Gly Gly Gly Gly Ser Ala Pro Leu Gly Gly Pro Glu 100 105 110 Pro Ala Gln Tyr Glu Glu Leu Thr Leu Leu Phe His Gly Ala Leu Gln 115 120 125 Leu Gly Gln Ala Leu Asn Gly Val Tyr Arg Ala Thr Glu Ala Arg Leu 130 135 140 Thr Glu Ala Gly His Ser Leu Gly Leu Tyr Asp Arg Ala Leu Glu Phe 145 150 155 160 Leu Gly Thr Glu Val Arg Gln Gly Gln Asp Ala Thr Gln Glu Leu Arg 165 170 175 Thr Ser Leu Ser Glu Ile Gln Val Glu Glu Asp Ala Leu His Leu Arg 180 185 190 Ala Glu Ala Thr Ala Arg Ser Leu Gly Glu Val Ala Arg Ala Gln Gln 195 200 205 Ala Leu Arg Asp Thr Val Arg Arg Leu Gln Val Gln Leu Arg Gly Ala 210 215 220 Trp Leu Gly Gln Ala His Gln Glu Phe Glu Thr Leu Lys Ala Arg Ala 225 230 235 240 Asp Lys Gln Ser His Leu Leu Trp Ala Leu Thr Gly His Val Gln Arg 245 250 255 Gln Gln Arg Glu Met Ala Glu Gln Gln Gln Trp Leu Arg Gln Ile Gln 260 265 270 Gln Arg Leu His Thr Ala Ala Leu Pro Ala Gly Gly Gly Gly Ser Trp 275 280 285 His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala 290 295 300 Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp 305 310 315 320 Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Ser Tyr Met 325 330 335 Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly 340 345 350 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 355 360 365 Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gin Thr Phe Thr 370 375 380 Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val 385 390 395 400 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 405 410 415 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Lys Pro 420 425 430 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 435 440 445 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 450 455 460 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 465 470 475 480 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 485 490 495 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 500 505 510 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 515 520 525 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 530 535 540 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 545 550 555 560 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 565 570 575 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 580 585 590 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 595 600 605 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 610 615 620 Ser Leu Ser Leu Ser Pro Gly Lys 625 630 <210> 141 <211> 646 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 141 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Gly Gly Gly Gly Ser Phe Pro Thr Ile Pro Leu Ser 100 105 110 Arg Leu Phe Asp Asn Ala Met Leu Arg Ala His Arg Leu His Gln Leu 115 120 125 Ala Phe Asp Thr Tyr Gln Glu Phe Glu Glu Ala Tyr Ile Pro Lys Glu 130 135 140 Gln Lys Tyr Ser Phe Leu Gln Asn Pro Gln Thr Ser Leu Cys Phe Ser 145 150 155 160 Glu Ser Ile Pro Thr Pro Ser Asn Arg Glu Glu Thr Gln Gln Lys Ser 165 170 175 Asn Leu Glu Leu Leu Arg Ile Ser Leu Leu Leu Ile Gln Ser Trp Leu 180 185 190 Glu Pro Val Gln Phe Leu Arg Ser Val Phe Ala Asn Ser Leu Val Tyr 195 200 205 Gly Ala Ser Asp Ser Asn Val Tyr Asp Leu Leu Lys Asp Leu Glu Glu 210 215 220 Gly Ile Gln Thr Leu Met Gly Arg Leu Glu Asp Gly Ser Pro Arg Thr 225 230 235 240 Gly Gln Ile Phe Lys Gln Thr Tyr Ser Lys Phe Asp Thr Asn Ser His 245 250 255 Asn Asp Asp Ala Leu Leu Lys Asn Tyr Gly Leu Leu Tyr Cys Phe Arg 260 265 270 Lys Asp Met Asp Lys Val Glu Thr Phe Leu Arg Ile Val Gln Cys Arg 275 280 285 Ser Val Glu Gly Ser Cys Gly Phe Gly Gly Gly Gly Ser Trp His Val 290 295 300 Asp Val Trp Gly Gin Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr 305 310 315 320 Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser 325 330 335 Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu 340 345 350 Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His 355 360 365 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 370 375 380 Met Val Thr Val Pro Gly Ser Thr Ser Gly Gin Thr Phe Thr Cys Asn 385 390 395 400 Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro 405 410 415 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 420 425 430 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 435 440 445 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 450 455 460 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 465 470 475 480 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 485 490 495 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 500 505 510 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 515 520 525 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 530 535 540 Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn 545 550 555 560 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 565 570 575 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 580 585 590 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 595 600 605 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 610 615 620 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 625 630 635 640 Ser Leu Ser Pro Gly Lys 645 <210> 142 <211> 621 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 142 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Gly Gly Gly Gly Ser Met Ser Tyr Asn Leu Leu Gly 100 105 110 Phe Leu Gln Arg Ser Ser Asn Phe Gln Cys Gln Lys Leu Leu Trp Gln 115 120 125 Leu Asn Gly Arg Leu Glu Tyr Cys Leu Lys Asp Arg Met Asn Phe Asp 130 135 140 Ile Pro Glu Glu Ile Lys Gln Leu Gln Gln Phe Gln Lys Glu Asp Ala 145 150 155 160 Ala Leu Thr Ile Tyr Glu Met Leu Gln Asn Ile Phe Ala Ile Phe Arg 165 170 175 Gln Asp Ser Ser Ser Thr Gly Trp Asn Glu Thr Ile Val Glu Asn Leu 180 185 190 Leu Ala Asn Val Tyr His Gln Ile Asn His Leu Lys Thr Val Leu Glu 195 200 205 Glu Lys Leu Glu Lys Glu Asp Phe Thr Arg Gly Lys Leu Met Ser Ser 210 215 220 Leu His Leu Lys Arg Tyr Tyr Gly Arg Ile Leu His Tyr Leu Lys Ala 225 230 235 240 Lys Glu Tyr Ser His Cys Ala Trp Thr Ile Val Arg Val Glu Ile Leu 245 250 255 Arg Asn Phe Tyr Phe Ile Asn Arg Leu Thr Gly Tyr Leu Arg Asn Gly 260 265 270 Gly Gly Gly Ser Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val 275 280 285 Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser 290 295 300 Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu 305 310 315 320 Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly 325 330 335 Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 340 345 350 Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser 355 360 365 Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys 370 375 380 Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 385 390 395 400 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 405 410 415 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 420 425 430 Val Thr Cys Val Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 435 440 445 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 450 455 460 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 465 470 475 480 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 485 490 495 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 500 505 510 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 515 520 525 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 530 535 540 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 545 550 555 560 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 565 570 575 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 580 585 590 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 595 600 605 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 610 615 620 <210> 143 <211> 646 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 143 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Gly Gly Gly Gly Ser Phe Pro Thr Ile Pro Leu Ser 100 105 110 Arg Leu Phe Asp Asn Ala Met Leu Arg Ala His Arg Leu His Gln Leu 115 120 125 Ala Phe Asp Thr Tyr Gln Glu Phe Glu Glu Ala Tyr Ile Pro Lys Glu 130 135 140 Gln Lys Tyr Ser Phe Leu Gln Asn Pro Gln Thr Ser Leu Cys Phe Ser 145 150 155 160 Glu Ser Ile Pro Thr Pro Ser Asn Arg Glu Glu Thr Gln Gln Lys Ser 165 170 175 Asn Leu Glu Leu Leu Arg Ile Ser Leu Leu Leu Ile Gln Ser Trp Leu 180 185 190 Glu Pro Val Gln Phe Leu Arg Ser Val Phe Ala Asn Ser Leu Val Tyr 195 200 205 Gly Ala Ser Asp Ser Asn Val Tyr Asp Leu Leu Lys Asp Leu Glu Glu 210 215 220 Gly Ile Gln Thr Leu Met Gly Arg Leu Glu Asp Gly Ser Pro Arg Thr 225 230 235 240 Gly Gln Ile Phe Lys Gln Thr Tyr Ser Lys Phe Asp Thr Asn Ser His 245 250 255 Asn Asp Asp Ala Leu Leu Lys Asn Tyr Gly Leu Leu Tyr Cys Phe Arg 260 265 270 Lys Asp Met Asp Lys Val Glu Thr Phe Leu Arg Ile Val Gln Cys Arg 275 280 285 Ser Val Glu Gly Ser Cys Gly Phe Gly Gly Gly Gly Ser Trp His Val 290 295 300 Asp Val Trp Gly Gin Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr 305 310 315 320 Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser 325 330 335 Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu 340 345 350 Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His 355 360 365 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 370 375 380 Met Val Thr Val Pro Gly Ser Thr Ser Gly Gin Thr Phe Thr Cys Asn 385 390 395 400 Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro 405 410 415 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 420 425 430 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 435 440 445 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 450 455 460 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 465 470 475 480 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 485 490 495 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 500 505 510 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 515 520 525 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 530 535 540 Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn 545 550 555 560 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 565 570 575 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 580 585 590 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 595 600 605 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 610 615 620 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 625 630 635 640 Ser Leu Ser Pro Gly Lys 645 <210> 144 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (1)..(14) <223> Any positively charged or hydrophobic amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 144 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 <210> 145 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (1)..(7) <223> Any positively charged or hydrophobic amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 145 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 <210> 146 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (1)..(2) <223> Any hydrophobic amino acid <220> <221> MOD_RES <222> (3)..(3) <223> Any polar, uncharged amino acid <220> <221> MOD_RES <222> (4)..(4) <223> Any hydrophobic amino acid <220> <221> MOD_RES <222> (5)..(11) <223> Any positively charged or hydrophobic amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 146 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 <210> 147 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (1)..(2) <223> Any hydrophobic amino acid <220> <221> MOD_RES <222> (3)..(3) <223> Any polar, uncharged amino acid <220> <221> MOD_RES <222> (4)..(4) <223> Any hydrophobic amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 147 Xaa Xaa Xaa Xaa Ala Lys Leu Ala Ala Leu Lys 1 5 10 <210> 148 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 148 Ala Lys Leu Ala Ala Leu Lys 1 5 <210> 149 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 149 Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys 1 5 10 <210> 150 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 150 Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala Leu Lys 1 5 10 <210> 151 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 151 Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala 1 5 10 15 Leu Lys <210> 152 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 152 Cys Ala Ala Leu Lys Ser Lys Val Ser Ala Leu Lys Ser Lys Val Ala 1 5 10 15 Ser Leu Lys Ser Lys Val Ala Ala Leu 20 25 <210> 153 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 153 Ala Leu Lys Lys Glu Leu Gln Ala Asn Lys Lys Glu Leu Ala Gln Leu 1 5 10 15 Lys Lys Glu Leu Gln Ala Leu Lys Lys Glu Leu Ala Gln 20 25 <210> 154 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (1)..(14) <223> Any negatively charged or hydrophobic amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 154 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 <210> 155 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (1)..(7) <223> Any positively charged or hydrophobic amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 155 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 <210> 156 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (1)..(7) <223> Any positively charged or hydrophobic amino acid <220> <221> MOD_RES <222> (8)..(9) <223> Any hydrophobic amino acid <220> <221> MOD_RES <222> (10)..(10) <223> Any polar, uncharged amino acid <220> <221> MOD_RES <222> (11)..(11) <223> Any hydrophobic amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 156 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 <210> 157 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (8)..(9) <223> Any hydrophobic amino acid <220> <221> MOD_RES <222> (10)..(10) <223> Any polar, uncharged amino acid <220> <221> MOD_RES <222> (11)..(11) <223> Any hydrophobic amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 157 Glu Leu Ala Ala Leu Glu Ala Xaa Xaa Xaa Xaa 1 5 10 <210> 158 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 158 Glu Leu Ala Ala Leu Glu Ala 1 5 <210> 159 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 159 Glu Leu Ala Ala Leu Glu Ala Asn Gly Gly Ser Gly 1 5 10 <210> 160 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 160 Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala 1 5 10 <210> 161 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 161 Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly 1 5 10 15 Ser Gly <210> 162 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 162 Leu Ala Ala Val Glu Ser Glu Leu Ser Ala Val Glu Ser Glu Leu Ala 1 5 10 15 Ser Val Glu Ser Glu Leu Ala Ala Cys 20 25 <210> 163 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 163 Gln Leu Glu Lys Lys Leu Gln Ala Leu Glu Lys Lys Leu Ala Gln Leu 1 5 10 15 Glu Lys Lys Asn Gln Ala Leu Glu Lys Lys Leu Ala Gln 20 25 <210> 164 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 164 Cys Ala Ala Leu Lys Ser Lys Val Ser Ala Leu Lys Ser Lys Val Ala 1 5 10 15 Ser Leu Lys Ser Lys Val Ala Ala Leu 20 25 <210> 165 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 165 Leu Ala Ala Val Glu Ser Glu Leu Ser Ala Val Glu Ser Glu Leu Ala 1 5 10 15 Ser Val Glu Ser Glu Leu Ala Ala Cys 20 25 <210> 166 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 166 Ala Leu Lys Lys Glu Leu Gln Ala Asn Lys Lys Glu Leu Ala Gln Leu 1 5 10 15 Lys Lys Glu Leu Gln Ala Leu Lys Lys Glu Leu Ala Gln 20 25 <210> 167 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 167 Gln Leu Glu Lys Lys Leu Gln Ala Leu Glu Lys Lys Leu Ala Gln Leu 1 5 10 15 Glu Lys Lys Asn Gln Ala Leu Glu Lys Lys Leu Ala Gln 20 25 <210> 168 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 168 Leu Lys Leu Glu Leu Gln Leu Ile Lys Gln Tyr Arg Glu Ala Leu 1 5 10 15 <210> 169 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 169 Leu Ala Lys Ile Leu Glu Asp Glu Glu Lys His Ile Glu Trp Leu 1 5 10 15 <210> 170 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 170 Leu Ser Asp Leu His Arg Gln Val Ser Arg Leu Val 1 5 10 <210> 171 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 171 Leu Gln Asp Ala Lys Val Leu Leu Glu Ala Ala Leu 1 5 10 <210> 172 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 172 Leu Gln Gln Lys Ile His Glu Leu Glu Gly Leu Ile Ala Gln His 1 5 10 15 <210> 173 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 173 Ala Ala Gln Ile Arg Asp Gln Leu His Gln Leu Arg Glu Leu Phe 1 5 10 15 <210> 174 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 174 Glu Leu Ala Arg Leu Ile Arg Leu Tyr Phe Ala Leu 1 5 10 <210> 175 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 175 Gln Glu Ser Leu Tyr Val Asp Leu Phe Asp Lys Phe 1 5 10 <210> 176 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> Any hydrophobic amino acid <220> <221> MOD_RES <222> (4)..(4) <223> Any polar, uncharged amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 176 Xaa Xaa Xaa Xaa One <210> 177 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (2)..(4) <223> Any hydrophobic amino acid <220> <221> MOD_RES <222> (5)..(5) <223> Any polar, uncharged amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 177 Cys Xaa Xaa Xaa Xaa 1 5 <210> 178 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> Any hydrophobic amino acid <220> <221> MOD_RES <222> (4)..(4) <223> Any polar, uncharged amino acid <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 178 Xaa Xaa Xaa Xaa Cys 1 5 <210> 179 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 179 Gly Gly Gly Gly Ser 1 5 <210> 180 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 180 Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 <210> 181 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 181 Gly Gly Gly Gly Ser Gly Gly Gly Ser 1 5 <210> 182 <211> 12 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 182 atcgaaggtc gt 12 <210> 183 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 183 Ile Glu Gly Arg One <210> 184 <211> 12 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 184 cgtaaaaaac gt 12 <210> 185 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 185 Arg Lys Lys Arg One <210> 186 <211> 522 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 186 accccccttg gccctgcccg atccctgccc cagagcttcc tgctcaagtg cttagagcaa 60 gtgaggaaaa tccaggctga tggcgccgag ctgcaggaga ggctgtgtgc cgcccacaag 120 ctgtgccacc cggaggagct gatgctgctc aggcactctc tgggcatccc ccaggctccc 180 ctaagcagct gctccagcca gtccctgcag ctgacgagct gcctgaacca actacacggc 240 ggcctctttc tctaccaggg cctcctgcag gccctggcgg gcatctcccc agagctggcc 300 cccaccttgg acacactgca gctggacgtc actgactttg ccacgaacat ctggctgcag 360 atggaggacc tgggggcggc ccccgctgtg cagcccaccc agggcgccat gccgaccttc 420 acttcagcct tccaacgcag agcaggaggg gtcctggttg cttcccagct gcatcgtttc 480 ctggagctgg cataccgtgg cctgcgctac cttgctgagc cc 522 <210> 187 <211> 534 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 187 gccacacctc tgggccccgc ctcctccctg cctcagagct ttctgctcaa atgtctggag 60 caggtgcgga agatccaggg cgacggcgcc gctctgcaag agaaactggt cagcgaatgc 120 gccacatata agctgtgtca ccccgaggaa ctggtcctct tgggccacag cctgggcatc 180 ccctgggccc ctctcagctc ctgcccctcc caagctctcc aactggctgg atgtctgtcc 240 caactgcact ccggcctctt cctgtaccag ggactcctcc aggctctcga agggatcagc 300 cccgaactgg gccccacact ggacaccttg caactcgatg tggccgattt cgccacaacc 360 atctggcagc agatggaaga actcggaatg gctcctgctc tccagcccac acagggagct 420 atgcctgctt tcgcctctgc tttccagcgg agagctggtg gtgtgctcgt cgcatcccac 480 ctccagagct tcttggaggt gtcctatcgg gtgctccggc atctggccca accc 534 <210> 188 <211> 117 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 188 cacggagaag gaacatttac cagcgacctc agcaagcaga tggaggaaga ggccgtgagg 60 ctgttcatcg agtggctgaa gaacggcgga ccctcctctg gcgctccacc ccctagc 117 <210> 189 <211> 102 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 189 atcaacgtga agtgcagcct gccccagcag tgcatcaagc cctgcaagga cgccggcatg 60 cggttcggca agtgcatgaa caagaagtgc aggtgctaca gc 102 <210> 190 <211> 108 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 190 gccgctgcaa tctcctgcgt cggcagcccc gaatgtcctc ccaagtgccg ggctcaggga 60 tgcaagaacg gcaagtgtat gaaccggaag tgcaagtgct actattgc 108 <210> 191 <211> 90 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 191 catgcggaag gcacctttac cagcgatgtg agcagctatc tggaaggcca ggcggcgaaa 60 gaatttattg cgtggctggt gaaaggccgc 90 <210> 192 <211> 498 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 192 gccccaccac gcctcatctg tgacagccga gtcctggaga ggtacctctt ggaggccaag 60 gaggccgaga atatcacgac gggctgtgct gaacactgca gcttgaatga gaatatcact 120 gtcccagaca ccaaagttaa tttctatgcc tggaagagga tggaggtcgg gcagcaggcc 180 gtagaagtct ggcagggcct ggccctgctg tcggaagctg tcctgcgggg ccaggccctg 240 ttggtcaact cttcccagcc gtgggagccc ctgcagctgc atgtggataa agccgtcagt 300 ggccttcgca gcctcaccac tctgcttcgg gctctgggag cccagaagga agccatctcc 360 cctccagatg cggcctcagc tgctccactc cgaacaatca ctgctgacac tttccgcaaa 420 ctcttccgag tctactccaa tttcctccgg ggaaagctga agctgtacac aggggaggcc 480 tgcaggacag gggacaga 498 <210> 193 <211> 543 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 193 catccgattc cggatagcag cccgctgctg cagtttggcg gccaggtgcg ccagcgctat 60 ctgtataccg atgatgcgca gcagaccgaa gcgcatctgg aaattcgcga agatggcacc 120 gtgggcggcg cggcggatca gagcccggaa agcctgctgc agctgaaagc gctgaaaccg 180 ggcgtgattc agattctggg cgtgaaaacc agccgctttc tgtgccagcg cccggatggc 240 gcgctgtatg gcagcctgca ttttgatccg gaagcgtgca gctttcgcga actgctgctg 300 gaagatggct ataacgtgta tcagagcgaa gcgcatggcc tgccgctgca tctgccgggc 360 aacaaaagcc cgcatcgcga tccggcgccg cgcggcccgg cgcgctttct gccgctgccg 420 ggcctgccgc cggcgccgcc ggaaccgccg ggcattctgg cgccgcagcc gccggatgtg 480 ggcagcagcg atccgctgag catggtgggc ccgagccagg gccgcagccc gagctatgcg 540 agc 543 <210> 194 <211> 381 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 194 gcgccggcgc gcagcccgag cccgagcacc cagccgtggg aacatgtgaa cgcgattcag 60 gaagcgcgcc gcctgctgaa cctgagccgc gataccgcgg cggaaatgaa cgaaaccgtg 120 gaagtgatta gcgaaatgtt tgatctgcag gaaccgacct gcctgcagac ccgcctggaa 180 ctgtataaac agggcctgcg cggcagcctg accaaactga aaggcccgct gaccatgatg 240 gcgagccatt ataaacagca ttgcccgccg accccggaaa ccagctgcgc gacccagatt 300 attacctttg aaagctttaa agaaaacctg aaagattttc tgctggtgat tccgtttgat 360 tgctgggaac cggtgcagga a 381 <210> 195 <211> 498 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 195 atgagctata acctgctggg ctttctgcag cgcagcagca actttcagtg ccagaaactg 60 ctgtggcagc tgaacggccg cctggaatat tgcctgaaag atcgcatgaa ctttgatatt 120 ccggaagaaa ttaaacagct gcagcagttt cagaaagaag atgcggcgct gaccatttat 180 gaaatgctgc agaacatttt tgcgattttt cgccaggata gcagcagcac cggctggaac 240 gaaaccattg tggaaaacct gctggcgaac gtgtatcatc agattaacca tctgaaaacc 300 gtgctggaag aaaaactgga aaaagaagat tttacccgcg gcaaactgat gagcagcctg 360 catctgaaac gctattatgg ccgcattctg cattatctga aagcgaaaga atatagccat 420 tgcgcgtgga ccattgtgcg cgtggaaatt ctgcgcaact tttattttat taaccgcctg 480 accggctatc tgcgcaac 498 <210> 196 <211> 111 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 196 cactctcagg gtaccttcac ctctgactac tctaaatacc tggactctcg tcgtgctcag 60 gacttcgttc agtggctgat gaacaccaaa cgtaaccgta acaacatcgc t 111 <210> 197 <211> 438 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 197 gttccaattc aaaaggttca agatgatacc aaaactctga ttaaaactat tgtcacgcgt 60 ataaacgaca tcagccatac ccagtcggtt agctcaaagc aaaaagttac cggtttggac 120 tttattccgg gactgcaccc gatcctgacc cttagtaaaa tggaccagac actggccgtc 180 taccagcaaa tcctgacatc gatgccatcc agaaatgtga tacaaattag caacgatttg 240 gaaaaccttc gcgatctgct gcacgtgctg gccttcagta agtcctgtca tctgccgtgg 300 gcgtcgggac tggagactct tgactcgctg ggtggagtgt tagaggcctc tggctattct 360 actgaagtcg ttgcgctgtc acgcctccag gggagcctgc aggacatgct gtggcagctg 420 gacctgtcac ctggctgc 438 <210> 198 <211> 534 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 198 gctcctctgg gcggtcctga accagcacag tacgaggaac tgacactgtt gttccatgga 60 gccttgcagc tgggccaggc cctcaacggc gtgtaccgcg ccacagaggc acgtttgacc 120 gaggccggac acagcctggg tttgtacgac agagccctgg agtttctggg taccgaagtg 180 cgtcagggcc aggacgcaac tcaggagctg agaacctccc tctctgagat ccaggtggag 240 gaggacgccc tgcacctgcg cgccgaggcg acagcacgct ctttgggaga agttgctcgc 300 gctcagcagg ccctgcgtga taccgtgcgg agactccaag ttcagctcag aggcgcttgg 360 ctcggacagg cgcatcagga gttcgagacc ctgaaagctc gtgccgacaa acagtcccac 420 ctgctgtggg cgctcaccgg tcacgtccag cgccagcaac gcgaaatggc cgagcagcag 480 caatggctgc gccaaatcca gcagcgcctg cataccgcgg ccctgccagc gtaa 534 <210> 199 <211> 330 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 199 aacctgggtc tggactgcga cgaacactct tctgaatctc gttgctgccg ttaccccgctg 60 accgttgact tcgaggcgtt cggttgggac tggatcatcg ctccgaaacg ttacaaagct 120 aactactgct ctggtcagtg cgaatacatg ttcatgcaga aatacccgca cacccacctg 180 gttcagcagg ctaacccgcg tggttctgct ggtccgtgct gcaccccgac caaaatgtct 240 ccgatcaaca tgctgtactt caacgacaaa cagcagatca tctacggtaa aatcccgggt 300 atggttgttg accgttgcgg ttgctcttaa 330 <210> 200 <211> 1162 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 200 ggatccggtg gtttcaccat caaactgctg ctgttcatcg ttccgctggt tatctcttct 60 cgtatcgacc aggacaactc ttctttcgac tctctgtctc cggaaccgaa atctcgtttc 120 gctatgctgg acgacgttaa aatcctggct aacggtctgc tgcagctggg tcacggtctg 180 aaagacttcg ttcacaaaac caaaggtcag atcaacgaca tcttccagaa actgaacatc 240 ttcgaccagt ctttctacga cctgtctctg cagacctctg aaatcaaaga agaagaaaaa 300 gaactgcgtc gtaccaccta caaactgcag gttaaaaacg aagaagttaa aaacatgtct 360 ctggaactga actctaaact ggaatctctg ctggaagaaa aaatcctgct gcagcagaaa 420 gttaaatacc tggaagaaca gctgaccaac ctgatccaga accagccgga aaccccggaa 480 cacccggaag ttacctctct gaaaaccttc gttgaaaaac aggacaactc tatcaaagac 540 ctgctgcaga ccgttgaaga ccagtacaaa cagctgaacc agcagcactc tcagatcaaa 600 gaaatcgaaa accagctgcg tcgtacctct atccaggaac cgaccgaaat ctctctgtct 660 tctaaaccgc gtgctccgcg taccaccccg ttcctgcagc tgaacgaaat ccgtaacgtt 720 aaacacgacg gtatcccggc tgaatgcacc accatctaca accgtggtga acacacctct 780 ggtatgtacg ctatccgtcc gtctaactct caggttttcc acgtttactg cgacgttatc 840 tctggttctc cgtggaccct gatccagcac cgtatcgacg gttctcagaa cttcaacgaa 900 acctgggaaa actacaaata cggtttcggt cgtctggacg gtgaattctg gctgggtctg 960 gaaaaaatct actctatcgt taaacagtct aactacgttc tgcgtatcga actggaagac 1020 tggaaagaca acaaacacta catcgaatac tctttctacc tgggtaacca cgaaaccaac 1080 tacaccctgc acctggttgc tatcaccggt aacgttccga acgctatccc gaagaagaag 1140 aagaaaaaaa agaagaagaa at 1162 <210> 201 <211> 573 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 201 ttcccaacca ttcccttatc caggcttttt gacaacgcta tgctccgcgc ccatcgtctg 60 caccagctgg cctttgacac ctaccaggag tttgaagaag cctatatccc aaaggaacag 120 aagtattcat tcctgcagaa cccccagacc tccctctgtt tctcagagtc tattccgaca 180 ccctccaaca gggaggaaac acaacagaaa tccaacctag agctgctccg catctccctg 240 ctgctcatcc agtcgtggct ggagcccgtg cagttcctca ggagtgtctt cgccaacagc 300 ctggtgtacg gcgcctctga cagcaacgtc tatgacctcc taaaggacct agaggaaggc 360 atccaaacgc tgatggggag gctggaagat ggcagccccc ggactgggca gatcttcaag 420 cagacctaca gcaagttcga cacaaactca cacaacgatg acgcactact caagaactac 480 gggctgctct actgcttcag gaaggacatg gacaaggtcg agacattcct gcgcatcgtg 540 cagtgccgct ctgtggaggg cagctgtggc ttc 573 <210> 202 <211> 495 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 202 tgtgatctgc ctcaaaccca cagcctgggt agcaggagga ccttgatgct cctggcacag 60 atgaggagaa tctctctttt ctcctgcttg aaggacagac atgactttgg atttccccag 120 gaggagtttg gcaaccagtt ccaaaaggct gaaaccatcc ctgtcctcca tgagatgatc 180 cagcagatct tcaatctctt cagcacaaag gactcatctg ctgcttggga tgagaccctc 240 ctagacaaat tctacactga actctaccag cagctgaatg acctggaagc ctgtgtgata 300 cagggggtgg gggtgacaga gactcccctg atgaaggagg actccattct ggctgtgagg 360 aaatacttcc aaagaatcac tctctatctg aaagagaaga aatacagccc ttgtgcctgg 420 gaggttgtca gagcagaaat catgagatct ttttctttgt caacaaactt gcaagaaagt 480 ttaagaagta aggaa 495 <210> 203 <211> 170 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 203 ctgaaatgtt accaacatgg taaagttgtg acttgtcatc gagatatgaa gttttgctat 60 cataacactg gcatgccttt tcgaaatctc aagctcatcc tacagggatg ttcttcttcg 120 tgcagtgaaa cagaaaacaa taagtgttgc tcaacagaca gatgcaacaa 170 <210> 204 <211> 252 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 204 tctgtgagtg aaatacagct tatgcataac ctgggaaaac atctgaactc gatggagaga 60 gtagaatggc tgcgtaagaa gctgcaggat gtgcacaatt ttgttgccct tggagctcct 120 ctagctccca gagatgctgg ttcccagagg ccccgaaaaa aggaagacaa tgtcttggtt 180 gagagccatg aaaaaagtct tggagaggca gacaaagctg atgtgaatgt attaactaaa 240 gctaaatccc ag 252 <210> 205 <211> 597 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 205 atgaactgcg tgtgccgcct ggtgctggtg gtgctgagcc tgtggccgga taccgcggtg 60 gcgccgggcc cgccgccggg cccgccgcgc gtgagcccgg atccgcgcgc ggaactggat 120 agcaccgtgc tgctgacccg cagcctgctg gcggataccc gccagctggc ggcgcagctg 180 cgcgataaat ttccggcgga tggcgatcat aacctggata gcctgccgac cctggcgatg 240 agcgcgggcg cgctgggcgc gctgcagctg ccgggcgtgc tgacccgcct gcgcgcggat 300 ctgctgagct atctgcgcca tgtgcagtgg ctgcgccgcg cgggcggcag cagcctgaaa 360 accctggaac cggaactggg caccctgcag gcgcgcctgg atcgcctgct gcgccgcctg 420 cagctgctga tgagccgcct ggcgctgccg cagccgccgc cggatccgcc ggcgccgccg 480 ctggcgccgc cgagcagcgc gtggggcggc attcgcgcgg cgctggcgat tctgggcggc 540 ctgcatctga ccctggattg ggcggtgcgc ggcctgctgc tgctgaaaac ccgcctg 597 <210> 206 <211> 183 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 206 gactcttgga tggaagaagt tatcaaactg tgcggtcgtg aactggttcg tgctcagatc 60 gctatctgcg gtatgtctac ctggtctggt ggcggtcgtg gcggtcgtca gctgtactct 120 gctctggcta acaaatgctg ccacgttggt tgcaccaaac gttctctggc tcgtttctgc 180 taa 183 <210> 207 <211> 489 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 207 gatagctgga tggaagaagt gattaaactg tgcggccgcg aactggtgcg cgcgcagatt 60 gcgatttgcg gcatgagcac ctggagcatt gaaggccgca gcctgagcca ggaagatgcg 120 ccgcagaccc cgcgcccggt ggcggaaatt gtgccgagct ttattaacaa agataccgaa 180 accattaaca tgatgagcga atttgtggcg aacctgccgc aggaactgaa actgaccctg 240 agcgaaatgc agccggcgct gccgcagctg cagcagcatg tgccggtgct gaaagatagc 300 agcctgctgt ttgaagaatt taaaaaactg attcgcaacc gccagagcga agcggcggat 360 agcagcccga gcgaactgaa atatctgggc ctggataccc atagcattga aggccgccag 420 ctgtatagcg cgctggcgaa caaatgctgc catgtgggct gcaccaaacg cagcctggcg 480 cgcttttgc 489 <210> 208 <211> 306 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 208 agcctgagcc aggaagatgc gccgcagacc ccgcgcccgg tggcggaaat tgtgccgagc 60 tttattaaca aagataccga aaccattaac atgatgagcg aatttgtggc gaacctgccg 120 caggaactga aactgaccct gagcgaaatg cagccggcgc tgccgcagct gcagcagcat 180 gtgccggtgc tgaaagatag cagcctgctg tttgaagaat ttaaaaaact gattcgcaac 240 cgccagagcg aagcggcgga tagcagcccg agcgaactga aatatctggg cctggatacc 300 catagc 306 <210> 209 <211> 135 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 209 gactcttgga tggaagaagt tatcaaactg tgcggtcgtg aactggttcg tgctcagatc 60 gctatctgcg gtatgtctac ctggtctaaa cgttctctgt ctcaggaaga cgctccgcag 120 accccgcgtc cggtt 135 <210> 210 <211> 72 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 210 cagctgtact ctgctctggc taacaaatgc tgccacgttg gttgcaccaa acgttctctg 60 gctcgtttct gc 72 <210> 211 <211> 222 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 211 ccgcgcagcg cgaaagaact gcgctgccag tgcattaaaa cctatagcaa accgtttcat 60 ccgaaattta ttaaagaact gcgcgtgatt gaaagcggcc cgcattgcgc gaacaccgaa 120 attattgtga aactgagcga tggccgcgaa ctgtgcctgg atccgaaaga aaactgggtg 180 cagcgcgtgg tggaaaaatt tctgaaacgc gcggaaaaca gc 222 <210> 212 <211> 75 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 212 tgcaaaggca aaggcgcgaa atgcagccgc ctgatgtatg attgctgcac cggcagctgc 60 cgcagcggca aatgc 75 <210> 213 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 213 gcgggctgca aaaacttttt ttggaaaacc tttaccagct gcggc 45 <210> 214 <211> 102 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 214 atgtgcatgc cgtgctttac caccgatcat cagatggcgc gcaaatgcga tgattgctgc 60 ggcggcaaag gccgcggcaa atgctatggc ccgcagtgcc tg 102 <210> 215 <211> 204 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 215 aaaccggtga gcctgagcta tcgctgcccg tgccgctttt ttgaaagcca tgtggcgcgc 60 gcgaacgtga aacatctgaa aattctgaac accccgaact gcgcgctgca gattgtggcg 120 cgcctgaaaa acaacaaccg ccaggtgtgc attgatccga aactgaaatg gattcaggaa 180 tatctggaaa aagcgctgaa caaa 204 <210> 216 <211> 399 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 216 cagggccagg atcgccatat gattcgcatg cgccagctga ttgatattgt ggatcagctg 60 aaaaactatg tgaacgatct ggtgccggaa tttctgccgg cgccggaaga tgtggaaacc 120 aactgcgaat ggagcgcgtt tagctgcttt cagaaagcgc agctgaaaag cgcgaacacc 180 ggcaacaacg aacgcattat taacgtgagc attaaaaaac tgaaacgcaa accgccgagc 240 accaacgcgg gccgccgcca gaaacatcgc ctgacctgcc cgagctgcga tagctatgaa 300 aaaaaaccgc cgaaagaatt tctggaacgc tttaaaagcc tgctgcagaa aatgattcat 360 cagcatctga gcagccgcac ccatggcagc gaagatagc 399 <210> 217 <211> 171 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 217 gcgcaagagc cagtcaaagg tccagtctcc actaagcctg gctcctgccc cattatcttg 60 atccggtgcg ccatgttgaa tccccctaac cgctgcttga aagatactga ctgcccagga 120 atcaagaagt gctgtgaagg ctcttgcggg atggcctgtt tcgttcccca g 171 <210> 218 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 218 atgtgtaccg caagcatacc accccaatgc tac 33 <210> 219 <211> 117 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 219 cacagccagg gcacattcac tagcgattat agtaaatatc tggattccaa ggcagcgcac 60 gattttgtag agtggctctt gaacggaggc ccttcctccg gagctccacc tccgtcc 117 <210> 220 <211> 117 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 220 cacggccagg gcacattcac tagcgattat agtaaatatc tggattccaa ggcagcgcac 60 gattttgtag agtggctctt gaacggaggc ccttcctccg gagctccacc tccgtcc 117 <210> 221 <211> 138 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 221 gctgacaaca aatgcgaaaa ctctctgcgt cgtgaaatcg cttgcggtca gtgccgtgac 60 aaagttaaaa ccgacggtta cttctacgaa tgctgcacct ctgactctac cttcaaaaaa 120 tgccaggacc tgctgcac 138 <210> 222 <211> 132 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 222 cacggcgacg gttcattctc tgacgaaatg aatacaatac tcgacaacct cgccgccagg 60 gactttatca attggctcat tcaaactaaa atcaccgacg gaggcccttc ctccggagct 120 ccacctccgt cc 132 <210> 223 <211> 555 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 223 gactcttgga tggaagaagt tatcaaactg tgcggtcgtg aactggttcg tgctcagatc 60 gctatctgcg gtatgtctac ctggtctaaa cgtggaggtg gcgggagcgg cacttctgag 120 tctgctactc cagaaagcgg cccaggttct gaaccagcaa cttctggctc tgagactcca 180 ggcacttctg agtccgcaac gcctgaatcc ggtcctggtt ctgaaccagc tacttccggc 240 agcgaaaccc caggtaccgg aggtggcggg agccaccatc accaccacca cggaggtggc 300 gggagctctg agtctgcgac tccagagtct ggtcctggta cttccactga gcctagcgag 360 ggttccgcac caggttctcc ggctggtagc ccgaccagca cggaggaggg tacgtctgaa 420 tctgcaacgc cggaatcggg cccaggttcg gagggaggag gtggcgggag ccgtaaaaaa 480 cgtcagctgt actctgctct ggctaacaaa tgctgccacg ttggttgcac caaacgttct 540 ctggctcgtt tctgc 555 <210> 224 <211> 360 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 224 gactcttgga tggaagaagt tatcaaactg tgcggtcgtg aactggttcg tgctcagatc 60 gctatctgcg gtatgtctac ctggtctaaa cgtggaggtg gcgggagctc tggcagcgaa 120 accccgggta cctccgaatc tgctacaccg gaaagcggtg gaggtggcgg gagccaccat 180 caccaccacc acggaggtgg cgggagccct ggcagccctg gtccgggcac tagcaccgag 240 ccatcggagg gctccgcacc aggaggtggc gggagccgta aaaaacgtca gctgtactct 300 gctctggcta acaaatgctg ccacgttggt tgcaccaaac gttctctggc tcgtttctgc 360 <210> 225 <211> 276 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 225 gactcttgga tggaagaagt tatcaaactg tgcggtcgtg aactggttcg tgctcagatc 60 gctatctgcg gtatgtctac ctggtctaaa cgtgaggcag aggacctgca ggtggggcag 120 gtggagctgg gcgggggccc tggtgcaggc agcctgcagc ccttggccct ggaggggtcc 180 ctgcagaagc gtcgtaaaaa acgtcagctg tactctgctc tggctaacaa atgctgccac 240 gttggttgca ccaaacgttc tctggctcgt ttctgc 276 <210> 226 <211> 222 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 226 gactcttgga tggaagaagt tatcaaactg tgcggtcgtg aactggttcg tgctcagatc 60 gctatctgcg gtatgtctac ctggtcttct ggcagcgaaa ccccgggtac ctccgaatct 120 gctacaccgg aaagcggtcc tggcagccct cagctgtact ctgctctggc taacaaatgc 180 tgccacgttg gttgcaccaa acgttctctg gctcgtttct gc 222 <210> 227 <211> 174 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 227 Thr Pro Leu Gly Pro Ala Arg Ser Leu Pro Gln Ser Phe Leu Leu Lys 1 5 10 15 Cys Leu Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu Gln 20 25 30 Glu Arg Leu Cys Ala Ala His Lys Leu Cys His Pro Glu Glu Leu Met 35 40 45 Leu Leu Arg His Ser Leu Gly Ile Pro Gln Ala Pro Leu Ser Ser Cys 50 55 60 Ser Ser Gln Ser Leu Gln Leu Thr Ser Cys Leu Asn Gln Leu His Gly 65 70 75 80 Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile Ser 85 90 95 Pro Glu Leu Ala Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Thr Asp 100 105 110 Phe Ala Thr Asn Ile Trp Leu Gln Met Glu Asp Leu Gly Ala Ala Pro 115 120 125 Ala Val Gln Pro Thr Gln Gly Ala Met Pro Thr Phe Thr Ser Ala Phe 130 135 140 Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser Gln Leu His Arg Phe 145 150 155 160 Leu Glu Leu Ala Tyr Arg Gly Leu Arg Tyr Leu Ala Glu Pro 165 170 <210> 228 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 228 His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Ser 35 <210> 229 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 229 Ile Asn Val Lys Cys Ser Leu Pro Gln Gln Cys Ile Lys Pro Cys Lys 1 5 10 15 Asp Ala Gly Met Arg Phe Gly Lys Cys Met Asn Lys Lys Cys Arg Cys 20 25 30 Tyr Ser <210> 230 <211> 36 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 230 Ala Ala Ala Ile Ser Cys Val Gly Ser Pro Glu Cys Pro Pro Lys Cys 1 5 10 15 Arg Ala Gln Gly Cys Lys Asn Gly Lys Cys Met Asn Arg Lys Cys Lys 20 25 30 Cys Tyr Tyr Cys 35 <210> 231 <211> 178 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 231 Ala Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu 1 5 10 15 Lys Cys Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu 20 25 30 Gln Glu Lys Leu Val Ser Glu Cys Ala Thr Tyr Lys Leu Cys His Pro 35 40 45 Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro 50 55 60 Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser 65 70 75 80 Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu 85 90 95 Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu 100 105 110 Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu 115 120 125 Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe 130 135 140 Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His 145 150 155 160 Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala 165 170 175 Gln Pro <210> 232 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 232 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg 20 25 30 <210> 233 <211> 165 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 233 Pro Pro Arg Leu Ile Cys Asp Ser Arg Val Leu Glu Arg Tyr Leu Leu 1 5 10 15 Glu Ala Lys Glu Ala Glu Asn Ile Thr Thr Gly Cys Ala Glu His Cys 20 25 30 Ser Leu Asn Glu Asn Ile Thr Val Pro Asp Thr Lys Val Asn Phe Tyr 35 40 45 Ala Trp Lys Arg Met Glu Val Gly Gln Gln Ala Val Glu Val Trp Gln 50 55 60 Gly Leu Ala Leu Leu Ser Glu Ala Val Leu Arg Gly Gln Ala Leu Leu 65 70 75 80 Val Asn Ser Ser Gln Pro Trp Glu Pro Leu Gln Leu His Val Asp Lys 85 90 95 Ala Val Ser Gly Leu Arg Ser Leu Thr Thr Leu Leu Arg Ala Leu Gly 100 105 110 Ala Gln Lys Glu Ala Ile Ser Pro Asp Ala Ala Ser Ala Ala Pro 115 120 125 Leu Arg Thr Ile Thr Ala Asp Thr Phe Arg Lys Leu Phe Arg Val Tyr 130 135 140 Ser Asn Phe Leu Arg Gly Lys Leu Lys Leu Tyr Thr Gly Glu Ala Cys 145 150 155 160 Arg Thr Gly Asp Arg 165 <210> 234 <211> 181 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 234 His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val 1 5 10 15 Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His 20 25 30 Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser 35 40 45 Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln 50 55 60 Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly 65 70 75 80 Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg 85 90 95 Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His 100 105 110 Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro 115 120 125 Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro 130 135 140 Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val 145 150 155 160 Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser 165 170 175 Pro Ser Tyr Ala Ser 180 <210> 235 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 235 Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val 1 5 10 15 Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr 20 25 30 Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp 35 40 45 Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln 50 55 60 Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met 65 70 75 80 Ala Ser His Tyr Lys Gln His Cys Pro Thr Pro Glu Thr Ser Cys 85 90 95 Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp 100 105 110 Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu 115 120 125 <210> 236 <211> 166 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 236 Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln 1 5 10 15 Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr Cys Leu 20 25 30 Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln 35 40 45 Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln 50 55 60 Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn 65 70 75 80 Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn 85 90 95 His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr 100 105 110 Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg 115 120 125 Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr 130 135 140 Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu 145 150 155 160 Thr Gly Tyr Leu Arg Asn 165 <210> 237 <211> 37 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 237 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn 20 25 30 Arg Asn Asn Ile Ala 35 <210> 238 <211> 146 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 238 Val Pro Ile Gln Lys Val Gln Asp Asp Thr Lys Thr Leu Ile Lys Thr 1 5 10 15 Ile Val Thr Arg Ile Asn Asp Ile Ser His Thr Gln Ser Val Ser Ser 20 25 30 Lys Gln Lys Val Thr Gly Leu Asp Phe Ile Pro Gly Leu His Pro Ile 35 40 45 Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln Ile 50 55 60 Leu Thr Ser Met Pro Ser Arg Asn Val Ile Gln Ile Ser Asn Asp Leu 65 70 75 80 Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys 85 90 95 His Leu Pro Trp Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 100 105 110 Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 115 120 125 Leu Gln Gly Ser Leu Gln Asp Met Leu Trp Gln Leu Asp Leu Ser Pro 130 135 140 Gly Cys 145 <210> 239 <211> 177 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 239 Ala Pro Leu Gly Gly Pro Glu Pro Ala Gln Tyr Glu Glu Leu Thr Leu 1 5 10 15 Leu Phe His Gly Ala Leu Gln Leu Gly Gln Ala Leu Asn Gly Val Tyr 20 25 30 Arg Ala Thr Glu Ala Arg Leu Thr Glu Ala Gly His Ser Leu Gly Leu 35 40 45 Tyr Asp Arg Ala Leu Glu Phe Leu Gly Thr Glu Val Arg Gln Gly Gln 50 55 60 Asp Ala Thr Gln Glu Leu Arg Thr Ser Leu Ser Glu Ile Gln Val Glu 65 70 75 80 Glu Asp Ala Leu His Leu Arg Ala Glu Ala Thr Ala Arg Ser Leu Gly 85 90 95 Glu Val Ala Arg Ala Gln Gln Ala Leu Arg Asp Thr Val Arg Arg Leu 100 105 110 Gln Val Gln Leu Arg Gly Ala Trp Leu Gly Gln Ala His Gln Glu Phe 115 120 125 Glu Thr Leu Lys Ala Arg Ala Asp Lys Gln Ser His Leu Leu Trp Ala 130 135 140 Leu Thr Gly His Val Gln Arg Gln Gln Arg Glu Met Ala Glu Gln Gln 145 150 155 160 Gln Trp Leu Arg Gln Ile Gln Gln Arg Leu His Thr Ala Ala Leu Pro 165 170 175 Ala <210> 240 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 240 Asn Leu Gly Leu Asp Cys Asp Glu His Ser Ser Glu Ser Arg Cys Cys 1 5 10 15 Arg Tyr Pro Leu Thr Val Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile 20 25 30 Ile Ala Pro Lys Arg Tyr Lys Ala Asn Tyr Cys Ser Gly Gln Cys Glu 35 40 45 Tyr Met Phe Met Gln Lys Tyr Pro His Thr His Leu Val Gln Gln Ala 50 55 60 Asn Pro Arg Gly Ser Ala Gly Pro Cys Cys Thr Pro Thr Lys Met Ser 65 70 75 80 Pro Ile Asn Met Leu Tyr Phe Asn Asp Lys Gln Gln Ile Ile Tyr Gly 85 90 95 Lys Ile Pro Gly Met Val Val Asp Arg Cys Gly Cys Ser 100 105 <210> 241 <211> 387 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 241 Gly Ser Gly Gly Phe Thr Ile Lys Leu Leu Leu Phe Ile Val Pro Leu 1 5 10 15 Val Ile Ser Ser Arg Ile Asp Gln Asp Asn Ser Ser Phe Asp Ser Leu 20 25 30 Ser Pro Glu Pro Lys Ser Arg Phe Ala Met Leu Asp Asp Val Lys Ile 35 40 45 Leu Ala Asn Gly Leu Leu Gln Leu Gly His Gly Leu Lys Asp Phe Val 50 55 60 His Lys Thr Lys Gly Gln Ile Asn Asp Ile Phe Gln Lys Leu Asn Ile 65 70 75 80 Phe Asp Gln Ser Phe Tyr Asp Leu Ser Leu Gln Thr Ser Glu Ile Lys 85 90 95 Glu Glu Glu Lys Glu Leu Arg Arg Thr Thr Tyr Lys Leu Gln Val Lys 100 105 110 Asn Glu Glu Val Lys Asn Met Ser Leu Glu Leu Asn Ser Lys Leu Glu 115 120 125 Ser Leu Leu Glu Glu Lys Ile Leu Leu Gln Gln Lys Val Lys Tyr Leu 130 135 140 Glu Glu Gln Leu Thr Asn Leu Ile Gln Asn Gln Pro Glu Thr Pro Glu 145 150 155 160 His Pro Glu Val Thr Ser Leu Lys Thr Phe Val Glu Lys Gln Asp Asn 165 170 175 Ser Ile Lys Asp Leu Leu Gln Thr Val Glu Asp Gln Tyr Lys Gln Leu 180 185 190 Asn Gln Gln His Ser Gln Ile Lys Glu Ile Glu Asn Gln Leu Arg Arg 195 200 205 Thr Ser Ile Gln Glu Pro Thr Glu Ile Ser Leu Ser Ser Lys Pro Arg 210 215 220 Ala Pro Arg Thr Thr Pro Phe Leu Gln Leu Asn Glu Ile Arg Asn Val 225 230 235 240 Lys His Asp Gly Ile Pro Ala Glu Cys Thr Thr Ile Tyr Asn Arg Gly 245 250 255 Glu His Thr Ser Gly Met Tyr Ala Ile Arg Pro Ser Asn Ser Gln Val 260 265 270 Phe His Val Tyr Cys Asp Val Ile Ser Gly Ser Pro Trp Thr Leu Ile 275 280 285 Gln His Arg Ile Asp Gly Ser Gln Asn Phe Asn Glu Thr Trp Glu Asn 290 295 300 Tyr Lys Tyr Gly Phe Gly Arg Leu Asp Gly Glu Phe Trp Leu Gly Leu 305 310 315 320 Glu Lys Ile Tyr Ser Ile Val Lys Gln Ser Asn Tyr Val Leu Arg Ile 325 330 335 Glu Leu Glu Asp Trp Lys Asp Asn Lys His Tyr Ile Glu Tyr Ser Phe 340 345 350 Tyr Leu Gly Asn His Glu Thr Asn Tyr Thr Leu His Leu Val Ala Ile 355 360 365 Thr Gly Asn Val Pro Asn Ala Ile Pro Lys Lys Lys Lys Lys Lys Lys Lys 370 375 380 Lys Lys Lys 385 <210> 242 <211> 191 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 242 Phe Pro Thr Ile Pro Leu Ser Arg Leu Phe Asp Asn Ala Met Leu Arg 1 5 10 15 Ala His Arg Leu His Gln Leu Ala Phe Asp Thr Tyr Gln Glu Phe Glu 20 25 30 Glu Ala Tyr Ile Pro Lys Glu Gln Lys Tyr Ser Phe Leu Gln Asn Pro 35 40 45 Gln Thr Ser Leu Cys Phe Ser Glu Ser Ile Pro Thr Pro Ser Asn Arg 50 55 60 Glu Glu Thr Gln Gln Lys Ser Asn Leu Glu Leu Leu Arg Ile Ser Leu 65 70 75 80 Leu Leu Ile Gln Ser Trp Leu Glu Pro Val Gln Phe Leu Arg Ser Val 85 90 95 Phe Ala Asn Ser Leu Val Tyr Gly Ala Ser Asp Ser Asn Val Tyr Asp 100 105 110 Leu Leu Lys Asp Leu Glu Glu Gly Ile Gln Thr Leu Met Gly Arg Leu 115 120 125 Glu Asp Gly Ser Pro Arg Thr Gly Gln Ile Phe Lys Gln Thr Tyr Ser 130 135 140 Lys Phe Asp Thr Asn Ser His Asn Asp Asp Ala Leu Leu Lys Asn Tyr 145 150 155 160 Gly Leu Leu Tyr Cys Phe Arg Lys Asp Met Asp Lys Val Glu Thr Phe 165 170 175 Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe 180 185 190 <210> 243 <211> 165 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 243 Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr Leu Met 1 5 10 15 Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser Cys Leu Lys Asp 20 25 30 Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln Phe Gln 35 40 45 Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln Ile Phe 50 55 60 Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu Thr Leu 65 70 75 80 Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp Leu Glu 85 90 95 Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu Met Lys 100 105 110 Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile Thr Leu 115 120 125 Tyr Leu Lys Glu Lys Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val Val Arg 130 135 140 Ala Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln Glu Ser 145 150 155 160 Leu Arg Ser Lys Glu 165 <210> 244 <211> 56 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 244 Leu Lys Cys Tyr Gln His Gly Lys Val Val Thr Cys His Arg Asp Met 1 5 10 15 Lys Phe Cys Tyr His Asn Thr Gly Met Pro Phe Arg Asn Leu Lys Leu 20 25 30 Ile Leu Gln Gly Cys Ser Ser Ser Cys Ser Glu Thr Glu Asn Asn Lys 35 40 45 Cys Cys Ser Thr Asp Arg Cys Asn 50 55 <210> 245 <211> 84 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 245 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 Ala Lys Ser Gln <210> 246 <211> 199 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 246 Met Asn Cys Val Cys Arg Leu Val Leu Val Val Leu Ser Leu Trp Pro 1 5 10 15 Asp Thr Ala Val Ala Pro Gly Pro Pro Pro Gly Pro Pro Arg Val Ser 20 25 30 Pro Asp Pro Arg Ala Glu Leu Asp Ser Thr Val Leu Leu Thr Arg Ser 35 40 45 Leu Leu Ala Asp Thr Arg Gln Leu Ala Ala Gln Leu Arg Asp Lys Phe 50 55 60 Pro Ala Asp Gly Asp His Asn Leu Asp Ser Leu Pro Thr Leu Ala Met 65 70 75 80 Ser Ala Gly Ala Leu Gly Ala Leu Gln Leu Pro Gly Val Leu Thr Arg 85 90 95 Leu Arg Ala Asp Leu Leu Ser Tyr Leu Arg His Val Gln Trp Leu Arg 100 105 110 Arg Ala Gly Gly Ser Ser Leu Lys Thr Leu Glu Pro Glu Leu Gly Thr 115 120 125 Leu Gln Ala Arg Leu Asp Arg Leu Leu Arg Arg Leu Gln Leu Leu Met 130 135 140 Ser Arg Leu Ala Leu Pro Gln Pro Pro Pro Asp Pro Pro Ala Pro Pro 145 150 155 160 Leu Ala Pro Ser Ser Ala Trp Gly Gly Ile Arg Ala Ala Leu Ala 165 170 175 Ile Leu Gly Gly Leu His Leu Thr Leu Asp Trp Ala Val Arg Gly Leu 180 185 190 Leu Leu Leu Lys Thr Arg Leu 195 <210> 247 <211> 60 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 247 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Gly Gly Gly 20 25 30 Arg Gly Gly Arg Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His 35 40 45 Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 50 55 60 <210> 248 <211> 163 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 248 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Ile Glu Gly 20 25 30 Arg Ser Leu Ser Gln Glu Asp Ala Pro Gln Thr Pro Arg Pro Val Ala 35 40 45 Glu Ile Val Pro Ser Phe Ile Asn Lys Asp Thr Glu Thr Ile Asn Met 50 55 60 Met Ser Glu Phe Val Ala Asn Leu Pro Gln Glu Leu Lys Leu Thr Leu 65 70 75 80 Ser Glu Met Gln Pro Ala Leu Pro Gln Leu Gln Gln His Val Pro Val 85 90 95 Leu Lys Asp Ser Ser Leu Leu Phe Glu Glu Phe Lys Lys Leu Ile Arg 100 105 110 Asn Arg Gln Ser Glu Ala Ala Asp Ser Ser Pro Ser Glu Leu Lys Tyr 115 120 125 Leu Gly Leu Asp Thr His Ser Ile Glu Gly Arg Gln Leu Tyr Ser Ala 130 135 140 Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala 145 150 155 160 Arg Phe Cys <210> 249 <211> 102 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 249 Ser Leu Ser Gln Glu Asp Ala Pro Gln Thr Pro Arg Pro Val Ala Glu 1 5 10 15 Ile Val Pro Ser Phe Ile Asn Lys Asp Thr Glu Thr Ile Asn Met Met 20 25 30 Ser Glu Phe Val Ala Asn Leu Pro Gln Glu Leu Lys Leu Thr Leu Ser 35 40 45 Glu Met Gln Pro Ala Leu Pro Gln Leu Gln Gln His Val Pro Val Leu 50 55 60 Lys Asp Ser Ser Leu Leu Phe Glu Glu Phe Lys Lys Leu Ile Arg Asn 65 70 75 80 Arg Gln Ser Glu Ala Ala Asp Ser Ser Pro Ser Glu Leu Lys Tyr Leu 85 90 95 Gly Leu Asp Thr His Ser 100 <210> 250 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 250 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 20 25 <210> 251 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 251 Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys 20 <210> 252 <211> 74 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 252 Pro Arg Ser Ala Lys Glu Leu Arg Cys Gln Cys Ile Lys Thr Tyr Ser 1 5 10 15 Lys Pro Phe His Pro Lys Phe Ile Lys Glu Leu Arg Val Ile Glu Ser 20 25 30 Gly Pro His Cys Ala Asn Thr Glu Ile Ile Val Lys Leu Ser Asp Gly 35 40 45 Arg Glu Leu Cys Leu Asp Pro Lys Glu Asn Trp Val Gln Arg Val Val 50 55 60 Glu Lys Phe Leu Lys Arg Ala Glu Asn Ser 65 70 <210> 253 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 253 Cys Lys Gly Lys Gly Ala Lys Cys Ser Arg Leu Met Tyr Asp Cys Cys 1 5 10 15 Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25 <210> 254 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 254 Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Gly 1 5 10 15 <210> 255 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 255 Met Cys Met Pro Cys Phe Thr Thr Asp His Gln Met Ala Arg Lys Cys 1 5 10 15 Asp Asp Cys Cys Gly Gly Lys Gly Arg Gly Lys Cys Tyr Gly Pro Gln 20 25 30 Cys Leu <210> 256 <211> 68 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 256 Lys Pro Val Ser Leu Ser Tyr Arg Cys Pro Cys Arg Phe Phe Glu Ser 1 5 10 15 His Val Ala Arg Ala Asn Val Lys His Leu Lys Ile Leu Asn Thr Pro 20 25 30 Asn Cys Ala Leu Gln Ile Val Ala Arg Leu Lys Asn Asn Asn Arg Gln 35 40 45 Val Cys Ile Asp Pro Lys Leu Lys Trp Ile Gln Glu Tyr Leu Glu Lys 50 55 60 Ala Leu Asn Lys 65 <210> 257 <211> 133 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 257 Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile 1 5 10 15 Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu 20 25 30 Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser 35 40 45 Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu 50 55 60 Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser 65 70 75 80 Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys 85 90 95 Asp Ser Tyr Glu Lys Lys Pro Lys Glu Phe Leu Glu Arg Phe Lys 100 105 110 Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His 115 120 125 Gly Ser Glu Asp Ser 130 <210> 258 <211> 57 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 258 Ala Gln Glu Pro Val Lys Gly Pro Val Ser Thr Lys Pro Gly Ser Cys 1 5 10 15 Pro Ile Ile Leu Ile Arg Cys Ala Met Leu Asn Pro Pro Asn Arg Cys 20 25 30 Leu Lys Asp Thr Asp Cys Pro Gly Ile Lys Lys Cys Cys Glu Gly Ser 35 40 45 Cys Gly Met Ala Cys Phe Val Pro Gln 50 55 <210> 259 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 259 Met Cys Thr Ala Ser Ile Pro Gln Cys Tyr 1 5 10 <210> 260 <211> 43 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 260 Ile Glu Gly Arg His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys 1 5 10 15 Tyr Leu Asp Ser Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Asn 20 25 30 Gly Gly Pro Ser Ser Gly Ala Pro Pro Ser 35 40 <210> 261 <211> 43 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 261 Ile Glu Gly Arg His Gly Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys 1 5 10 15 Tyr Leu Asp Ser Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Asn 20 25 30 Gly Gly Pro Ser Ser Gly Ala Pro Pro Ser 35 40 <210> 262 <211> 46 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 262 Ala Asp Asn Lys Cys Glu Asn Ser Leu Arg Arg Glu Ile Ala Cys Gly 1 5 10 15 Gln Cys Arg Asp Lys Val Lys Thr Asp Gly Tyr Phe Tyr Glu Cys Cys 20 25 30 Thr Ser Asp Ser Thr Phe Lys Lys Cys Gln Asp Leu Leu His 35 40 45 <210> 263 <211> 48 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 263 Ile Glu Gly Arg His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr 1 5 10 15 Ile Leu Asp Asn Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln 20 25 30 Thr Lys Ile Thr Asp Gly Gly Pro Ser Ser Gly Ala Pro Pro Ser 35 40 45 <210> 264 <211> 185 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 264 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Lys Arg Gly 20 25 30 Gly Gly Gly Ser Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro 35 40 45 Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu 50 55 60 Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly 65 70 75 80 Ser Glu Thr Pro Gly Thr Gly Gly Gly Gly Ser His His His His His 85 90 95 His Gly Gly Gly Gly Ser Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro 100 105 110 Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala 115 120 125 Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro 130 135 140 Glu Ser Gly Pro Gly Ser Glu Gly Gly Gly Gly Gly Ser Arg Lys Lys 145 150 155 160 Arg Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys 165 170 175 Thr Lys Arg Ser Leu Ala Arg Phe Cys 180 185 <210> 265 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 265 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Lys Arg Gly 20 25 30 Gly Gly Gly Ser Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala 35 40 45 Thr Pro Glu Ser Gly Gly Gly Gly Gly Ser His His His His His His 50 55 60 Gly Gly Gly Gly Ser Pro Gly Ser Pro Gly Pro Gly Thr Ser Thr Glu 65 70 75 80 Pro Ser Glu Gly Ser Ala Pro Gly Gly Gly Gly Ser Arg Lys Lys Arg 85 90 95 Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 100 105 110 Lys Arg Ser Leu Ala Arg Phe Cys 115 120 <210> 266 <211> 92 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 266 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Lys Arg Glu 20 25 30 Ala Glu Asp Leu Gln Val Gly Gln Val Glu Leu Gly Gly Gly Pro Gly 35 40 45 Ala Gly Ser Leu Gln Pro Leu Ala Leu Glu Gly Ser Leu Gln Lys Arg 50 55 60 Arg Lys Lys Arg Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His 65 70 75 80 Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 85 90 <210> 267 <211> 74 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 267 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Ser Gly Ser 20 25 30 Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly 35 40 45 Ser Pro Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly 50 55 60 Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 65 70 <210> 268 <211> 840 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 268 caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60 acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120 ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180 cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300 gaaactaaga aataccagag ctgtcctgac ggctatcggg agagatctga ttgcagtaat 360 aggccagctt gtggcacatc cgactgctgt cgcgtgtctg tcttcgggaa ctgcctgact 420 accctgcctg tgtcctactc ttatacctac aattatgaat ggcatgtgga tgtctgggga 480 cagggcctgc tggtgacagt ctctagtgct tccacaactg caccaaaggt gtaccccctg 540 tcaagctgct gtggggacaa atcctctagt accgtgacac tgggatgcct ggtctcaagc 600 tatatgcccg agcctgtgac tgtcacctgg aactcaggag ccctgaaaag cggagtgcac 660 accttcccag ctgtgctgca gtcctctggc ctgtatagcc tgagttcaat ggtgacagtc 720 cccggcagta cttcagggca gaccttcacc tgtaatgtgg cccatcctgc cagctccacc 780 aaagtggaca aagcagtgga acccaaatct tgcgacggca gccatcacca tcatcatcac 840 <210> 269 <211> 825 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 269 caggtccagc tgagagagag cgggccttca ctggtccagc cttcacagac actgagcctg 60 acttgtactg cctccgggtt ttcactgtct gacaaggctg tgggatgggt ccgacaggca 120 ccagggaaag ctctggagtg gctgggaagt atcgataccg gcgggtcaac agggtacaac 180 cctggactga agtccagact gtctattact aaggacaatt ctaaaagtca ggtgtcactg 240 agcgtgagct ccgtcaccac agaggattct gcaacatact attgcactac cgtgcaccag 300 gaaacaagga aaacttgtag tgacggctat atcgcagtgg atagctgcgg acgaggacag 360 tccgacggat gcgtgaacga ttgcaatagc tgttactatg gatggcgaaa ctgccggaga 420 cagccagcaa ttcattcata cgagtttcat gtggatgctt gggggcgggg gctgctggtc 480 accgtctcct cagcttccac aactgcacca aaggtgtacc ccctgtcaag ctgctgtggg 540 gacaaatcct ctagtaccgt gacactggga tgcctggtct caagctatat gcccgagcct 600 gtgactgtca cctggaactc aggagccctg aaaagcggag tgcacacctt cccagctgtg 660 ctgcagtcct ctggcctgta tagcctgagt tcaatggtga cagtccccgg cagtacttca 720 gggcagacct tcacctgtaa tgtggcccat cctgccagct ccaccaaagt ggacaaagca 780 gtggaaccca aatcttgcga cggcagccat caccatcatc atcac 825 <210> 270 <211> 828 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 270 caggtccagc tgagggaatc cggcccatca ctggtcaagc cttcacagac actgagcctg 60 acatgtactg caagcgggtt ttcactgagt gacaaggcag tgggatgggt ccggagagca 120 ccaggaaaag ccctggagtg gctgggaacc acagatactg gaggatccgc cgcttacaac 180 cctggcctga agtcccggct gtctatcacc aaggacaact ctaaaagtca ggtgtcactg 240 agcgtgtcca atgtcgctac agaagattct gcaacttact attgtagctc cgtgactcag 300 aggacccacg tctctcgcag ttgtccagac gggtgcagtg acggagatgg ctgcgtggat 360 ggatgctgtt gctcagctta ccgatgttat acacccgggg tcagagacct gagctgcacc 420 tcatatagca ttacatacac ttacgaatgg aatgtggatg cttggggaca gggactgctg 480 gtgaccgtct cttcagcttc cacaactgca ccaaaggtgt accccctgtc aagctgctgt 540 ggggacaaat cctctagtac cgtgacactg ggatgcctgg tctcaagcta tatgcccgag 600 cctgtgactg tcacctggaa ctcaggagcc ctgaaaagcg gagtgcacac cttcccagct 660 gtgctgcagt cctctggcct gtatagcctg agttcaatgg tgacagtccc cggcagtact 720 tcagggcaga ccttcacctg taatgtggcc catcctgcca gctccaccaa agtggacaaa 780 gcagtggaac ccaaatcttg cgacggcagc catcaccatc atcatcac 828 <210> 271 <211> 280 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 271 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Cys Pro Asp Gly Tyr 100 105 110 Arg Glu Arg Ser Asp Cys Ser Asn Arg Pro Ala Cys Gly Thr Ser Asp 115 120 125 Cys Cys Arg Val Ser Val Phe Gly Asn Cys Leu Thr Thr Leu Pro Val 130 135 140 Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly 145 150 155 160 Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys 165 170 175 Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val 180 185 190 Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val 195 200 205 Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala 210 215 220 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val 225 230 235 240 Pro Gly Ser Thr Ser Gly Gin Thr Phe Thr Cys Asn Val Ala His Pro 245 250 255 Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp 260 265 270 Gly Ser His His His His His His 275 280 <210> 272 <211> 275 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 272 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Gln Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Ser Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Thr Val His Gln Glu Thr Arg Lys Thr Cys Ser Asp Gly Tyr Ile Ala 100 105 110 Val Asp Ser Cys Gly Arg Gly Gln Ser Asp Gly Cys Val Asn Asp Cys 115 120 125 Asn Ser Cys Tyr Tyr Gly Trp Arg Asn Cys Arg Arg Gln Pro Ala Ile 130 135 140 His Ser Tyr Glu Phe His Val Asp Ala Trp Gly Arg Gly Leu Leu Val 145 150 155 160 Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser 165 170 175 Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu 180 185 190 Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly 195 200 205 Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 210 215 220 Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser 225 230 235 240 Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys 245 250 255 Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp Gly Ser His His His 260 265 270 His His His 275 <210> 273 <211> 276 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 273 Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Arg Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Thr Thr Asp Thr Gly Gly Ser Ala Ala Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Asn Val Ala Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Ser 85 90 95 Ser Val Thr Gln Arg Thr His Val Ser Arg Ser Cys Pro Asp Gly Cys 100 105 110 Ser Asp Gly Asp Gly Cys Val Asp Gly Cys Cys Cys Ser Ala Tyr Arg 115 120 125 Cys Tyr Thr Pro Gly Val Arg Asp Leu Ser Cys Thr Ser Tyr Ser Ile 130 135 140 Thr Tyr Thr Tyr Glu Trp Asn Val Asp Ala Trp Gly Gln Gly Leu Leu 145 150 155 160 Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu 165 170 175 Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys 180 185 190 Leu Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser 195 200 205 Gly Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 210 215 220 Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr 225 230 235 240 Ser Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 245 250 255 Lys Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp Gly Ser His His 260 265 270 His His His His 275 <210> 274 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic 6xHis tag <400> 274 His His His His His His 1 5 <210> 275 <211> 100 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <220> <221> misc_feature <222> (1)..(100) <223> This sequence may encompass 1-20 'Gly Gly Gly Gly Ser' repeating units, wherein some positions may be absent <220> <223> See specification as filed for detailed description of substitutions and preferred embodiments <400> 275 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 35 40 45 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 50 55 60 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser 65 70 75 80 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 85 90 95 Gly Gly Gly Ser 100 <210> 276 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 276 Cys Gly Gly Gly Gly Ser 1 5 <210> 277 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 277 Gly Gly Gly Gly Ser Cys 1 5 <210> 278 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 278 Ile Glu Gly Arg Lys Lys Arg 1 5 <210> 279 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 279 Gly Gly Ser Gly One

Claims (101)

An immunoglobulin fusion protein comprising a non-antibody region located within a complementarity determining region (CDR) of a first antibody variable domain, wherein the non-antibody region comprises a first extender peptide comprising SEQ ID NO: 151, a first therapeutic agent; and a second extender peptide comprising SEQ ID NO: 161, wherein the first therapeutic agent is attached to the first antibody domain by a first extender peptide and a second extender peptide, and wherein the CDR is CDRL3, CDRH2 or CDRH3. globulin fusion protein. The immunoglobulin fusion protein of claim 1 , wherein the first therapeutic agent substitutes one or more amino acids of the first antibody domain. The immunoglobulin fusion protein of claim 1 , wherein said first antibody variable domain comprises an amino acid sequence selected from SEQ ID NOs: 19-36 and 271-273. The immunoglobulin fusion protein of claim 1 , wherein said first antibody variable domain comprises an amino acid sequence that is at least 90% identical to an amino acid sequence selected from SEQ ID NOs: 19-36 and 271-273. The immunoglobulin fusion protein of claim 1 , wherein the first antibody variable domain comprises an amino acid sequence based on or derived from a trastuzumab or palivizumab immunoglobulin. The immunoglobulin fusion protein of claim 1 , wherein the first antibody variable domain comprises an amino acid sequence based on or derived from a trastuzumab immunoglobulin. The immunoglobulin fusion protein of claim 1 , wherein said first antibody variable domain comprises an amino acid sequence based on or derived from palivizumab immunoglobulin. The immunoglobulin fusion protein of claim 1 , wherein said first therapeutic agent comprises an amino acid sequence selected from SEQ ID NOs: 227-267. The immunoglobulin fusion protein of claim 1 , wherein said first therapeutic agent comprises an amino acid sequence that is at least 90% identical to an amino acid sequence selected from SEQ ID NOs: 227-267. The immunoglobulin fusion protein of claim 1 , wherein the first therapeutic agent comprises GMCSF. The immunoglobulin fusion protein of claim 1 , wherein said first therapeutic agent comprises a sequence that is at least 90% identical to SEQ ID NO:235. The immunoglobulin fusion protein of claim 1 , wherein the first extender peptide comprises a linking peptide. The immunoglobulin fusion protein of claim 1 , wherein the second extender peptide comprises a linking peptide. A first gene construct comprising a nucleic acid encoding the immunoglobulin fusion protein of any one of claims 1-13. A pharmaceutical composition comprising the immunoglobulin fusion protein of any one of claims 1 to 13. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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